LJMU Research Online Mohammadhosseini, M, Venditti, A, Sarker, SD, Nahar, L and Akbarzadeh, A The genus Ferula: ethnobotany, phytochemistry and bioactivities - a review http://researchonline.ljmu.ac.uk/id/eprint/9786/ Article Citation (please note it is advisable to refer to the publisher’s version if you intend to cite from this work) Mohammadhosseini, M, Venditti, A, Sarker, SD, Nahar, L and Akbarzadeh, A (2018) The genus Ferula: ethnobotany, phytochemistry and bioactivities - a review. Industrial Crops and Products, 129. pp. 350-394. ISSN 0926-6690 LJMU has developed LJMU Research Online for users to access the research output of the University more effectively. Copyright © and Moral Rights for the papers on this site are retained by the individual authors and/or other copyright owners. Users may download and/or print one copy of any article(s) in LJMU Research Online to facilitate their private study or for non-commercial research. 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For more information please contact researchonline@ljmu.ac.uk http://researchonline.ljmu.ac.uk/ 1 The genus Ferula: ethnobotany, phytochemistry and 2 bioactivities - a review 3 4 Majid Mohammadhosseini1*, Alessandro Venditti2, Satyajit D. 5 Sarker3, Lutfun Nahar3, and Abolfazl Akbarzadeh4 6 7 8 9 1 Department of Chemistry, Shahrood Branch, Islamic Azad University, Shahrood, Iran Dipartimento di Chimica, Università di Roma “La Sapienza”, Piazzale Aldo Moro 5, 00185 Rome, Italy 2 3 12 Medicinal Chemistry and Natural Products Research Group, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, United Kingdom 13 4 10 11 14 Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran 15 16 *Corresponding author at: Department of Chemistry, Shahrood Branch, Islamic 17 Azad University, Shahrood, Iran. Tel: +98-023-32394530; Fax: +98-023- 18 32394537 19 E-mail addresses: 20 majidmohammadhosseini@yahoo.com; majidmohammadhosseini@gmail.com; 21 m_mhosseini@iau-shahrood.ac.ir (M. Mohammadhosseini) 1 22 The genus Ferula: ethnobotany, phytochemistry and bioactivities - a review 23 24 25 Table of Contents Abstract ................................................................................................................................................... 3 26 1. Introduction ......................................................................................................................................... 3 27 2. Research methodology ........................................................................................................................ 5 28 3. Ethnobotany and traditional usage of the Ferula species ................................................................... 6 29 4. Chemical profiles of the essential oils, extracts, resins and volatiles ……………………………...11 30 5. Phytochemistry of the Ferula species (2000 to March 2018) ........................................................... 15 31 5.1. Coumarin derivatives ................................................................................................................. 16 32 5.1.1. Hemiterpene coumarins .......................................................................................................... 16 33 5.1.2. Monoterpene coumarins.......................................................................................................... 16 34 5.1.3. Sesquiterpene coumarins ........................................................................................................ 17 35 5.1.4. Coumarinyl esters ................................................................................................................... 19 36 5.1.4.1. Dihydrofuranocoumarinyl esters.......................................................................................... 20 37 5.2. Prenylated benzoic acid derivatives ........................................................................................... 20 38 5.3. Sesquiterpene chromones........................................................................................................... 20 39 5.4. Sesquiterpenes............................................................................................................................ 21 40 5.5. Sulfur containing metabolites .................................................................................................... 24 41 5.6. Miscellaneous ............................................................................................................................ 25 42 7. The bioactivities of diverse characterized compounds from the genus Ferula................................. 28 43 7.1. Anti-HIV activity ....................................................................................................................... 29 44 7.2. Inhibitory activity on cytokine production................................................................................. 29 45 7.3. Inhibitory activity on NO production......................................................................................... 30 46 7.4. The inhibitory on Epstein-Barr virus early antigen (EBV-EA) activation................................. 30 47 7.5. Inhibitory against Plasmodium falciparum ................................................................................ 31 48 7.6. Antineuroinflammatory potential in LPS-activated BV-2 microglial cells ............................... 31 49 7.7. Cytotoxicity................................................................................................................................ 31 50 7.8. Antibacterial and antimicrobial activity ..................................................................................... 34 51 7.9. Anti-inflammatory activity ........................................................................................................ 36 52 7.10. Inhibitory behavior of transcription-activating factors for iNOS mRNA ................................ 36 53 7.11. Antiprolifertive/anticancer activity .......................................................................................... 37 54 7.12. Antioxidant activity ................................................................................................................. 40 55 7.13. The antileishmanial activity ..................................................................................................... 40 56 7.14. The ferulosis............................................................................................................................. 41 57 8. Propagation of Ferula species........................................................................................................... 44 2 58 9. Conclusion and future perspectives .................................................................................................. 47 59 Acknowledgments................................................................................................................................. 49 60 References ............................................................................................................................................. 51 61 62 Abstract 63 This study aims to provide a comprehensive overview of the medicinal, folkloric and 64 traditional culinary uses of Ferula species, related products and extracts in different countries 65 together with the description of recently isolated new components and the related 66 bioactivities. The phytochemical composition of the essential oils (EOs), oleo-gum-resin 67 (OGR) and the non-volatile fractions obtained from several endemic and indigenous Ferula 68 species is also reported. A special emphasis is placed on their unusual components, i.e. 69 sulfur-containing volatiles from the EOs and the new phytochemicals with mixed biogenetic 70 origins. More than 180 chemical constituents (excluding common essential oils components), 71 including sulfur-containing metabolites, terpenoids, coumarins, sesquiterpene coumarins, 72 etc., as both aglycones and glycosides, are reported, along with their occurrence and 73 biological activities when available. A large number of new secondary metabolites, belonging 74 to different classes of natural products possessing interesting biological activities, from the 75 antiproliferative to the anti-inflammatory to the neuroprotective ones, among the others, have 76 been recently found in the Ferula genus. Several of these phytochemicals are exclusive to 77 this genus; therefore may be considered chemotaxonomic markers. All these aspects are 78 extensively discussed in this review. 79 Keywords: Ferula spp.; Apiaceae; Ethnomedicine; Secondary metabolites; Traditional uses; 80 Essential oil; Non-volatile components 81 1. Introduction 3 82 The genus Ferula, the third largest genus of the Apiaceae (alt. Umbelliferae) family, is 83 composed of ca. 180 species (Yaqoob and Nawchoo, 2016), 15 of which are endemic to Iran 84 (Mozaffarian, 1996), nine species to Turkey, seven to China (Yaqoob and Nawchoo, 2016) 85 and one species to Italy (Conti et al, 2005), and the rest are indigenous entities of several 86 other countries. 87 The majority of the Ferula plants have a pungent odor and can be used for different purposes. 88 The endemic and indigenous species of the Ferula in the flora of some countries, of which 89 the data are available, are listed in Table 1. 90 In the literature, numerous reports have described various biological and medicinal activities 91 for different essential oils (EOs) and extracts of the Ferula plants. These include anticancer 92 (Paydar et al., 2013; Perveen et al., 2017; Upadhyay et al., 2017), anthelmintic (Kakar et al., 93 2013; Upadhyay et al., 2017), anti-epileptic (Sayyah et al., 2001; Kiasalari et al., 2013), 94 aphicidal (Stepanycheva et al., 2012), antioxidant (Kavoosi et al., 2013; Paydar et al., 2013; 95 Amiri, 2014; Znati et al., 2014; Lahazi et al., 2015; Moosavi et al., 2015; Yusufoglu et al., 96 2015c; Zhang et al., 2015; Nguir et al., 2016), antimicrobial (Yang et al., 2007; Kavoosi et 97 al., 2013; Liu et al., 2013; Paydar et al., 2013; Bashir et al., 2014b; Pavlovic et al., 2015), 98 antihypertensive (Ghanbari et al., 2012), antifungal (Rani et al., 2009; Al-Ja'Fari et al., 2013; 99 Bashir et al., 2014b; Upadhyay et al., 2017), antidepressant (Mohammadhosseini, 2016), 100 phytotoxic (Bashir et al., 2014b), (Kavoosi et al., 2013; Paydar et al., 2013; Pavlovic et al., 101 2015), antiproliferative (Poli et al., 2005; Moradzadeh et al., 2017), acetylcholinesterase 102 inhibitory (Adhami et al., 2014) and muscarinic receptors inhibitory (Khazdair et al., 2015), 103 antiprotozoal activity (El Deeb et al., 2012; Bafghi et al., 2014; Barati et al., 2014), 104 antihemolytic (Nabavi et al., 2011), antimycobacterial (Mossa et al., 2004; Fallah et al., 105 2015), anti-ulcer (Alqasoumi et al., 2011), antitumor (Zhang et al., 2015; Bagheri et al., 106 2017), anticoagulant (Lamnaouer, 1999; Fraigui et al., 2002), antifertility (Keshri et al., 4 107 1999), antispasmodic (Fatehi et al., 2004; Upadhyay et al., 2017), anticonvulsant (Sayyah and 108 Mandgary, 2003; Bagheri et al., 2014b), relaxant (Sadraei et al., 2001), antinociceptive 109 (Mandegary et al., 2004; Bagheri et al., 2014a), hypnotic (Abbasnia and Aeinfar, 2016), 110 hypotensive (Upadhyay et al., 2017), muscle relaxant (Upadhyay et al., 2017), memory 111 enhancing (Upadhyay et al., 2017), enhancing digestive enzyme (Upadhyay et al., 2017), 112 antiviral (Lee et al., 2009; Ghannadi et al., 2014; Upadhyay et al., 2017), anxiolytics 113 (Upadhyay et al., 2017), antihyperlipidemic (Yusufoglu et al., 2015a; Yusufoglu et al., 114 2015b), antigenotoxic (Hu et al., 2009; Abbasnia and Aeinfar, 2016), anti-inflammatory 115 (Mandegary et al., 2004; Paydar et al., 2013; Bagheri et al., 2015; Moosavi et al., 2015), 116 cytotoxic (Elouzi et al., 2008; Valiahdi et al., 2013; Gudarzi et al., 2015; Mohd Shafri et al., 117 2015; Hosseini et al., 2017), antihyperglycemic (Yusufoglu et al., 2015a; Yusufoglu et al., 118 2015b; Yusufoglu et al., 2015c), acaricidal (Fatemikia et al., 2017), antidiabetic (Yarizade et 119 al., 2017), hepatoprotective (Upadhyay et al., 2017) and antibiotic modulation (Paydar et al., 120 2013) activities. 121 In this review paper, we aim to cover the ethnobotany, phytochemistry and pharmacological 122 activities along with chemical composition of the essential oils (EOs), volatiles, oleo-gum- 123 resins (OGRs) and extracts of different species of the genus Ferula described in recent 124 decades. 125 2. Research methodology 126 To prepare a comprehensive phytochemical and ethnobotanical review on the plants of the 127 genus Ferula, the corresponding data were integrated in this report. To organize this review 128 paper, ISI-WOS, PubMed, Scopus (date of access: 18 September 2017 and revisited on 10 129 March 2018) and Google scholar databases, papers published in recent decades by publishers 130 such as Elsevier, Springer, Taylor and Francis and John Wiley, and English and non-English 5 131 reference books dealing with useful properties of the Ferula plants have been systematically 132 reviewed. 133 3. Ethnobotany and traditional usage of the Ferula species 134 Medicinal plants have been of prime importance in the folkloric traditional medicine systems 135 for centuries (Mohammadhosseini, 2017). The remedial properties of these plants are 136 remarkable (Mohammadhosseini et al., 2017a; Mohammadhosseini et al., 2017b). Due to the 137 unpleasant side effects and ineffectivness of many conventional drugs, the search for new 138 drugs from natural origin has gained momentum in recent years. 139 In this regard, different species of the genus Ferula have always been in the focus, 140 specifically in the Middle East and Asian countries including Iran, Pakistan, Iraq, India and 141 others. According to the flora of Iran, different Ferula species are widespread in eastern and 142 central parts of the country. Most Ferula species have a bitter taste and pungent odor. The 143 genus Ferula has a Latin root meaning “vehicle” or “carrier”. In Persian, “asa” means resin. 144 It is also noteworthy that the word “foetida” originates from the Latin word “foetidus” 145 meaning “smell” accounting for its pungent sulfur-based odor. In the folk medicine of Iran, 146 China, Germany, Italy, France and India, Asafoetida is often called "Anghouzeh", "A Wei", 147 "Teufellsdreck or Stinkasant", "Assafoetida", and "ase-fetide", respectively (Iranshahy and 148 Iranshahi, 2011). An oleo-gum-resin (OGR), as a milky and bitter substance, is exudated 149 from the stem of some Ferula plants, e.g. F. assa-foetida and F. gummosa Boiss. and 150 coagulates when exposed to the air. 151 The gum of the most important species of the genus Ferula, namely F. assa-foetida L. has 152 many therapeutic properties. Significant amounts of this gum are annually exported from Iran 153 and Afghanistan to the East Asian countries like China and Japan, via Mongolia, as well as to 154 European and North American countries. Many people believe that the sticky gum from F. 6 155 assa-foetida L. is a strong carminative agent that can remove the stomach worms. In children, 156 it is used as an antiparasite remedy. It has been reported that the roots of two species of 157 Ferula, namely F. assa-foetida L. (Fig. 1) and F. gummosa Boiss., are rich sources of 158 valuable natural compounds (Mozaffarian, 2012). The general properties of F. assa-foetida L. 159 in traditional medicine are reported to have potent antiseptic, antimucous, anti-epilepsy 160 (specifically in the children), anticonvulsant, antitetanus and aphrodisiac (see Table 2) 161 activities, and to be of value in the regulation of the menstruation, and as an antidote for 162 insect and animal bites (Mohammadhosseini, 2016). In the latter case, certain amount of the 163 gum is dissolved in olive oil and subsequently placed on the site of the bite. This can lower 164 the pain and considerably improve inflamed and infected wounds. The suspension of F. assa- 165 foetida L. can be used to repel wild animals. 166 The gum or decoctions of F. assa-foetida L. has been used to treat certain wounds, 167 hemorrhoids and rheumatism, and as a useful remedy to refine the liver blood in trade 168 markets. In addition, its pickling serves as an effective agent to remove some parasites from 169 the human body and it appears to have strong antiviral activity against influenza. 170 In some ancient civilizations, a necklace of F. assa-foetida L. was placed around the neck of 171 patients suffering from severe cold or hay fever. In traditional Persian medicine, people 172 believed that F. assa-foetida L. was effective in the treatment of a broad range of diseases 173 and disorders, and for this reason it was called “food of God”. Interestingly, among the 174 different stories about F. assa-foetida L., it was suggested that the name originates from the 175 idea of God’s semen fertilizing the earth. 176 This valuable species is widely used as an additive in foodstuffs. Some nomads of central 177 Iran still use fried F. assa-foetida L. along with some condiments as a carminative food. The 178 rural people and nomads of Semnan province (Abbas Abad Village, Shahrood, Iran) use the 179 dried aerial parts of F. assa-foetida L. in the preparation of their delicious local food, 7 180 “Loghri”, which also contains barley, Nagorno Qrvt (Qareh Qurut), tomato or tomato 181 paste, beans and other vegetables (Fig. 2). 182 There are myths of a spiritual nature that F. assa-foetida L. can strengthen the human body, 183 and repulse negative energy, evils and demons (Mahendra and Bisht, 2012). 184 Apart from some biological and medicinal properties, the spice prepared from F. assa-foetida 185 L. is regarded as an effective remedy for Angina pectoris (Srinivasan, 2005). 186 In Afghan folk medicine, the dried gum of F. assa-foetida is immersed in hot water and the 187 extract is used as an herbal drug to treat ulcers, whooping cough and hysteria (Mahran et al., 188 1973). 189 In Morocco, F. assa-foetida L. is reputed to be a magical anti-epileptic drug, and another 190 endemic species of Ferula (F. communis L.) has been regarded as an antispasmodic agent 191 with some degree of toxicity (Bellakhdar et al., 1991). 192 In Nepal, the resins of F. assa-foetida L. are extracted with water and the extract is used 193 orally as an anthelmintic agent (Bhattarai, 1992). In desert localities of Saudi Arabia, the 194 inhabitants utilize the gum of F. assa-foetida L. for treating asthma, bronchitis and cough 195 (Seabrook, 1927). 196 In Brazil, the hot water extract from the dried leaves and stems of F. assa-foetida L. are used 197 orally to treat erectile dysfunction, and as an aphrodisiac (Elisabetsky et al., 1992). 198 Moreover, the crushed powder obtained from an OGR of F. assa-foetida L. has been used as 199 a condiment in India for many years (Seetharam and Pasricha, 1987). 200 In USA, resin extracts of F. assa-foetida L. taken orally have been used as an antispasmodic, 201 expectorant, aphrodisiac and a stimulant for the human nervous system (Lilly, 1898). In 202 addition, the black American people reportedly use the gum of F. assa-foetida L. for many 203 purposes, e.g. cancer, menstruatal problems, asthma, convulsion, laryngitis, corns of the feet, 204 hand and foot callous and madness. In America, F. assa-foetida L. is prescribed as an 8 205 effective diuretic, stimulant and sedative phytoremedy. In addition to diverse medicinal uses, 206 different organs of F. assa-foetida L., either in fresh or dried form are used for cooking, as 207 even small parts of this plant can give a pungent smell to foodstuffs. It has also found many 208 applications as a condiment and flavoring agent in chocolates, seasoning and soft drinks. Due 209 to emmenagogue properties of F. assa-foetida L., it is not recommended in the breast-feeding 210 period and its overuse may cause abortion. Antipain, antitumor, digestive, lactating, 211 fungicide, mutagenic, uterus tonic are among the other properties attributed to this plant. It 212 also prevents platelet adhesion of the blood and lowers the fever and blood pressure. To treat 213 pneumonia, bronchitis, cough and cold, F. assa-foetida L. is often considered among the 214 frequently options in the folk medicine of many Asian countries. It is reported to cure 215 rheumatism, gout, hysteria, and sciatica. 216 The stem of F. gummosa Boiss. has numerous elliptical ducts dispersed in the phloem tissues. 217 In the vegetative stage of this plant, the OGR in these ducts is exuded manually or naturally 218 (Mortazaienezhad and Sadeghian, 2006). In fact, the gum of F. gummosa Boiss. is reported to 219 have numerous medicinal properties. When it is mixed with honey, it is said to aid removal of 220 large kidney and bladder stones. The diluted gum of this plant is used by the local midwifes 221 to expel the dead fetus. 222 In Iranian folk medicine, it is said that if the gum of F. gummosa Boiss. is dissolved in water 223 and drunk for three sequential days, it can treat hemorrhoids. Moreover, when this gum is 224 dissolved in nettle decoction and mixed with olive oil and put on painful places as a poultice, 225 it can decrease the severe pains of waist. In different European countries, the gum, called 226 galbanum, exuded from F. gummosa Boiss. has also been used to treat epilepsy, stomachache 227 and as an effective wound healing agent (Miyazawa et al., 2009). This material has also been 228 used as an anthelmintic agent and to treat diarrhea, constipation, and abdominal pains. In 229 Iranian folk medicine, the OGR (galbanum) from F. gummosa Boiss. has been widely 9 230 prescribed as an antispasmodic and stimulant to treat digestive disorders such as colic and 231 flatulence. It is also reported as a uterine tonic and to have expectorant properties in the 232 treatment of chronic bronchitis. 233 Another species of this genus, F. narthex Boiss, is found widespread in Pakistan, especially 234 in Gilgit and Chitral. The Pakistani people highly use this herbal plant or its gum resin to treat 235 hysteria, gastric malfunctions, cough, fever, the sting of scorpions, constipation and habitual 236 abortion as well as a strong sedative agent in painful toothaches (Bashir et al., 2013). 237 F. communis L., having two subspecies, namely F. communis subsp. communis and F. 238 communis subsp. glauca (Pesmen, 1972) has been used in Sardinian folk medicine on 239 account of reported antiseptic features of decoctions of its roots (Sanna et al., 2006; Maggi et 240 al., 2016; Rahali et al., 2016). It has been reported that in the ancient Rome, assa-foetida was 241 stored in jars with pine nuts which were used to give pleasant and specific flavors and odors 242 to certain foods, including vegetables, barbecued meats, meatballs, pickles and other cooked 243 dishes (Mahendra and Bisht, 2012; Mohammadhosseini, 2016). 244 During investigation of the chemistry and biology of the Umbelliferae plants (now Apiaceae), 245 French (1971) pointed out the reported antihysteric properties of F. communis L. and its 246 potential to treat dysentery. In fact, this species is a source of several medicinal and 247 pharmaceutical substances. According to the Greek mythology, F. communis L. (Narthex) 248 was employed by Prometheus, of Greek legend, to set fire to the earth where this species 249 grew (Gennadios, 1914). Despite the high toxicity of some chemotypes of this plant to 250 humans and animals (Marchi et al., 2003), it has been used to treat skin infections, dysentery 251 and fever (Al-Yahya et al., 1998). In a study of the hormonal impact of Ferula plants, F. 252 hermonis Boiss. has been introduced as containing a phytoestrogen having a high affinity 253 toward estrogen receptors and capable of having a positive impact on certain disorders (Ikeda 254 et al., 2002). 10 255 In Tunisian folk medicine, F. communis L., has been reported to treat foot cracks, joint pains, 256 parasitic worms, rheumatism, dysentery, hysteria and skin diseases (Nguir et al., 2016). 257 However, domestic animals fed with F. communis L. can develop haemorragic and ferulotic 258 diseases (Lamnaouer et al., 1991; Lamnaouer et al., 1994; Tanji and Nassif, 1995). 259 In the traditional medicine of Syria and Lebanon, F. hermonis Boiss. is called “Shirsh-el- 260 Zallouh,” which means “having a hairy root” on account of its general morphology. This 261 plant has been long used as an aphrodisiac agent (Table 2) in the treatment of impotence and 262 frigidity (Auzi et al., 2008; Al-Ja'Fari et al., 2011). 263 264 4. Chemical profiles of the essential oils, extracts, resins and volatiles from different Ferula species 265 Essential oil (EOs) are mixtures of natural compounds released from the secretory glands of a 266 wide array of plants. EOs are often used in a variety of the industrial disciplines. In addition, 267 EOs have a great impact on perfumery and fragrance enterprises. 268 Classical hydrodistillation (HD) and steam distillation (SD) have been used to extract EOs 269 since antiquity. However, within the last decades of the 20th century, microwave methods 270 have resulted in faster and more efficient separations of EOs. Accordingly, microwave- 271 assisted hydrodistillation (MAHD) (Mohammadhosseini et al., 2013; Hashemi-Moghaddam 272 et al., 2014; Hashemi-Moghaddam et al., 2015) along with solvent-free microwave extraction 273 (SFME) (Mohammadhosseini, 2015a; Nekoei and Mohammadhosseini, 2017), are now 274 considered to be effective and advanced approaches for the isolation of volatile EOs. 275 On the other hand, volatiles produced by different organs of plant materials can be released 276 thermally and can be directed onto the surface of diverse organic fibers (Mohammadhosseini, 277 2015b; Mohammadhosseini et al., 2016). The volatile parts can also be introduced directly 278 into the injection port of gas chromatographic-based devices (Mohammadhosseini et al., 279 2017a). 11 280 The main components in the chemical profiles of a vast number of EOs, extracts and volatiles 281 of the Ferula plants from 1989 to March 2018 are listed in Table 3. A careful perusal of 282 Table 3 reveals that the most abundant non-terpenoid hydrocarbons found in the reported 283 chemical profiles were sulfur-containing compounds involving (E)-1-propenyl-sec-butyl 284 disulfide, dimethyl-trisulphide, sec-butyl-(Z)-propenyl-disulphide, sec-butyl-(E)-propenyl- 285 disulphide, di-sec-butyl-disulphide, phenol 2-methyl-5-(1-methylethyl), trimethylthiophene, 286 2,5-diethylthiophene, 1-methylpropyl-(1E)-prop-1-en-1-yl-disulfide, 1-methylpropyl-(1Z)- 287 prop-1-en-1-yl-disulfide and bis-[(1-methylthio)propyl]-disulfide (Khajeh et al., 2005; 288 Iranshahi et al., 2006; Iranshahi et al., 2008; Dehpour et al., 2009; Sahebkar et al., 2010; 289 Kanani et al., 2011; Li et al., 2011; Kavoosi et al., 2012; Mirzaei and Hasanloo, 2012; 290 Kavoosi and Purfard, 2013; Kavoosi and Rowshan, 2013; Özek et al., 2017), along with 2- 291 methyl octane (Kanani et al., 2011), nonane (Baser et al., 2000; Kanani et al., 2011) and 292 aromatic derivatives (benzene-1-3-dimethyl etc.) (Sadraei et al., 2001; Chibani et al., 2012). 293 Furthermore, the most frequently occurring monoterpene hydrocarbons in the characterized 294 profiles were found to be α-pinene, β-pinene, limonene, p-cymene, γ-terpinene, δ-3-carene 295 and myrcene (Garg et al., 1989; Rustaiyan et al., 2001a; Sadraei et al., 2001; Sayyah and 296 Mandgary, 2003; Akhgar et al., 2005; Ferrari et al., 2005; Kose et al., 2010; Al-Ja'Fari et al., 297 2011; Kanani et al., 2011; Amiri, 2014; Bouratoua et al., 2014; Alipour et al., 2015; Ben 298 Salem et al., 2016; Schepetkin et al., 2016; Najafabadi et al., 2017; Znati et al., 2017). On the 299 other hand, oxygenated sesquiterpenes like carvacrol, neryl acetate, verbenone, thymol, cis- 300 chrysanthenol and camphor had the highest frequencies in the reported profiles (Ghannadi et 301 al., 2002; Chibani et al., 2012; Alipour et al., 2015). Moreover, germacrene D, 302 bicyclogermacrene, (E)-caryophyllene, α-gurjunene, δ-cadinene, γ-cadinene and γ-elemene 303 (Habibi et al., 2006a; Maggi et al., 2009a; Maggi et al., 2009b; Kanani et al., 2011; Bahramia 304 et al., 2013; Mohammadhosseini et al., 2015) were instead the dominant sesquiterpene 12 305 hydrocarbons. The major oxygenated sesquiterpenes contributing to the aforementioned 306 chemical profiles in Table 3 were α-cadinol, guaiol, (E)-nerolidol, α-eudesmol, (Z)- 307 ocimenone, (E)-ocimenone, viridiflorol, epi-α-muurolol, carotol, valerianol and hinesol 308 (Rustaiyan et al., 2001b; Shatar, 2005; Habibi et al., 2006b; Benchabane et al., 2012; Ozkan 309 et al., 2014; Labed-Zouad et al., 2015; Kasaian et al., 2016; Nguir et al., 2016). 310 In the search for compounds of chemotaxonomic relevance from species in the genus Ferula, 311 EOs of 23 populations relating to 18 species were screened (Kanani et al., 2011). Fig. 3, 312 shows the molecular structures of the most prevalent compounds recognized in that study. 313 The sulfur-containing compounds have the highest frequency and are responsible for the 314 specific odors of different Ferula species. Furthermore, a cluster analysis (Ward dendrogram) 315 of the most abundant components in the characterized profiles of the EOs of the Ferula 316 species revealed the presence of four groups, namely i) monoterpene hydrocarbons (first 317 cluster) consisting of α-pinene (52%-69%) as well as α-pinene (16-37%) and β-pinene (36- 318 66%) for the first and second subgroups, respectively; 319 ii) oxygenated monoterpenes (second cluster) involving α-terpinyl acetate (73%) and 320 sabinene (20%), verbenone (69%) and ar-curcumene (6%); 321 iii) organosulfur compounds (third cluster) including 2,3,4-trimethylthiophene (2) (49%), and 322 2,5-diethylthiophene (6) (28%); 323 iv) monoterpene + sesquiterpene + aliphatic hydrocarbons (fourth cluster) containing (Z)-β- 324 ocimene (42%), myrcene (35%), sabinene (75%) and (E)-caryophyllene (16%). 325 Maggi and collaborators (2009b) reported chemical profiles of the EOs from different parts, 326 e.g. flowers, fruits, roots and leaves of F. glauca L. growing wild in Marche (Central Italy). 327 In their study, EOs were obtained using classical hydrodistillation and were sequentially 328 analyzed using GC-FID and GC-MS techniques. A total of 74 constituents were 329 characterized, representing 87-95% of the total leaves oil. The predominant constituents were 13 330 sesquiterpene hydrocarbons that included (E)-caryophyllene, α-humulene and germacrene D, 331 respectively involving 16-25%, 10-18%, 7-9%, and 5-10% of the total chemical profile. 332 Furthermore, 95 compounds, accounting for 90-97% of the flower oils were identified. Once 333 again, sesquiterpene hydrocarbons dominated over the other groups, with (E)-caryophyllene 334 and germacrene D accounting, respectively, for 6-14% and 14-21% of the oil composition. 335 On the other hand, the analysis of the oil from the fruits of F. glauca L. revealed the presence 336 of a total of 55 components (69-90%). In contrast to the oils from the leaves and flowers of F. 337 glauca L., monoterpene hydrocarbons contributed to the profiles as the major fractions with 338 pinene derivatives (α: 24-45%; β: 15-20%) being the most abundant. Finally, in the essential 339 oil separated from the roots of F. glauca L., 54 compounds were identified altogether 340 accounting for 69-80% of the oil. Similar to the oil profile from the leaves and flowers of F. 341 glauca L., the root oil was rich in sesquiterpene hydrocarbons with (E)-β-farnesene and α- 342 zingiberene each accounting for 5-10% of the compounds. 343 Recently, Moghaddam and Farhadi (2015), have studied chemical compositions of nine 344 populations of F. assa-foetida L. growing wild in different localities of Kerman province, 345 Iran. As shown in Table 3, a total of 30 constituents, accounting for 96-99% of the oil, were 346 identified in the EOs of F. assa-foetida L. This study revealed the presence of some non- 347 terpene sulfur-containing hydrocarbons, namely (E)-propenyl,sec-butyl disulfide (37-54%), 348 (Z)-propenyl,sec-butyl disulfide (12-23%) and n-propyl,sec-butyl disulfide (0-5%) along with 349 lower quantities of some monoterpene hydrocarbons such as α-pinene (4-7%), β-pinene (8- 350 15%) and (E)-β-ocimene (3-6%). This study showed a great variation in the mean yields of 351 the resins from F. assa-foetida L. Moreover, a statistical analysis displayed a positive 352 correlation between the precipitation rates in the sampling area and the yield of the obtained 353 resins. In addition, a remarkable increase in the yield of the obtained resins was noted when 14 354 the temperature increased. Accordingly, the highest contents of EOs were found in localities 355 having the highest precipitation rates and altitude. 356 5. Phytochemistry of the Ferula species (2000 to March 2018) 357 In the literature, some reports occasionally discuss phytochemistry in addition to the 358 biological and medicinal properties of some species of the genus Ferula (Iranshahy and 359 Iranshahi, 2011; Sahebkar and Iranshahi, 2011; Zare et al., 2011; Kareparamban et al., 2012; 360 Akaberi et al., 2015; Amalraj and Gopi, 2017; Sattar and Iranshahi, 2017a, b; Upadhyay et 361 al., 2017; Zhou et al., 2017). However, the current review paper aims to give a deeper insight 362 into the major ethnopharmaceutical properties, along with chemical compositions of the 363 essential oils, organic extracts and volatiles from the different Ferula species growing wild 364 worldwide. In addition, the phytochemistry of the different species of this genus is discussed 365 over the period of 2000-to the present time (March 2018). It is also noteworthy that before 366 the year 2000, many reports were published relating to natural bioactive sulfur compounds 367 (Al-Said et al., 1996), triterpenes (Diaz et al., 1984; Díaz et al., 1984), sesquiterpene esters 368 (Miski et al., 1983; Miski et al., 1984; Razdan et al., 1989; Appendino et al., 1990; González 369 et al., 1993; Khalilova and Saidkhodzhaev, 1998a), sesquiterpene derivatives of the farnesyl- 370 benzofuranone type (Kojima et al., 1999), esters (Saidkhodzhaev et al., 1985a; 371 Saidkhodzhaev et al., 1985b; Golovina et al., 1987; Kerimov et al., 1987; Saidkhodzhaev et 372 al., 1993b; Saidkhodzhaev et al., 1993d; Kobilov et al., 1995b, a; Nazhimutdinova et al., 373 1995), isocarotane esters (Garg et al., 1998), daucane esters (Miski and Mabry, 1985; Miski 374 and Jakupovic, 1990; Appendino et al., 1997), sesquiterpene coumarins (Buddrus et al., 1985; 375 Nassar et al., 1995; Ahmed, 1999), sesquiterpene lactones (Kir'yalov and Serkerov, 1966; 376 Bagirov et al., 1979a, b; Bagirov et al., 1984; Sagitdinova et al., 1991; Serkerov et al., 1992; 377 Kabilov et al., 1994), terpenoids (Nazhimitdinova and Saidkhodzhaev, 1993; Saidkhodzhaev 15 378 et al., 1993a; Saidkhodzhaev and Mamatkhanov, 1995; Khalilova and Saidkhodzhaev, 379 1998b), and terpene coumarins (Vandyshev et al., 1974; Savina et al., 1978; Sokolova et al., 380 1978; Veselovskaya et al., 1979; Kir'yanova et al., 1980; Kuliev et al., 1980; Veselovskaya et 381 al., 1980; Sklyar et al., 1982; Veselovskaya et al., 1982; Nabiev and Malikov, 1983; Al- 382 Hazimi, 1986; Serkerov and Mir-Babaev, 1987; Saidkhodzhaev et al., 1991; Saidkhozhaev et 383 al., 1991; Saidkhodzhaev et al., 1993c). 384 In the recent decades, several natural products from different organs of a wide variety of the 385 Ferula plants have been reported. The sulfur-containing compounds in these plants are often 386 responsible for the pungent odors of the corresponding products. Furthermore, a large number 387 of phytochemical reports have revealed the presence of novel natural compounds in the 388 diverse species of the genus Ferula. In the following sub-sections, new identified metabolites 389 are reviewed and subdivided in classes of natural compounds. 390 391 5.1. Coumarin derivatives 392 393 5.1.1. Hemiterpene coumarins 394 A variety of coumarin derivatives were identified in the methanol extract obtained from the 395 dried roots of F. sumbul (Kauffm.) Hook.F. (Fig. 4), including two furanocoumarin esters: 396 fesumtuorin A (13) and fesumtuorin B (14); one bicoumarin, fesumtuorin C (15); five 397 spirobicoumarins, fesumtuorin D (16), fesumtuorin E (17), fesumtuorin F (18), fesumtuorin 398 G (19) and fesumtuorin H (20), in addition to nineteen known coumarins (Zhou et al., 2000). 399 400 5.1.2. Monoterpene coumarins 401 In a different work, the group by El-Razek (El-Razek et al., 2001) was able to separate two 402 monoterpene coumarins, namely ferulagol A (21) and ferulagol B (22) (Fig. 5) from a 403 dichloromethane extract of F. ferulago L. 16 404 405 5.1.3. Sesquiterpene coumarins 406 Six sesquiterpenoids, named pallidones A-F (23-28) (Fig. 6), together with two known 407 sesquiterpenes (feselol and conferol) already found in several Ferula species, were isolated 408 from the ethyl acetate extract of the roots of F. pallida Korovin (Su et al., 2000). The possible 409 biogenetic pathway of the sesquiterpene coumarins, pallidones A (23) and B (24) was also 410 discussed: A common biosynthetic precursor for pallidones A-F and other sesquiterpene- 411 coumarins was hypothesized in 2-hydroxy-4-methoxycinnamic acid. This might be involved 412 in two different pathways: one proceed through cyclization to form the coumarin skeleton, 413 the other implies the addition of water to the double bond and the subsequent oxidation of 414 hydroxyl function to constitute the appropriate intermediate, then both pathways imply the 415 reaction of condensation with the appropriate sesquiterpene derivative. 416 Assafoetidnol A (29) and assafoetidnol B (30) (Fig. 7) were reported by Abd El-Razek et al. 417 (2001) in the organic extracts prepared of the roots of F. assa-foetida L. in addition to six 418 other compounds, gummosin, polyanthin, badrakemin, neveskone, samarcandin and galbanic 419 acid. 420 Motai et al (2004) purified six sesquiterpene coumarin derivatives, 2,3-dihydro-7-hydroxy- 421 2R*,3R*-dimethyl-2-[4,8-dimethyl-3(E),7-nonadien-6-onyl]furo[3,2-c]coumarin 422 fukanefuromarin A (32), fukanefuromarin B (33), fukanefuromarin C (34), fukanefuromarin 423 D (35), and fukanemarin A (36) (Fig. 8), from the water-methanol extract of the roots of F. 424 fukanensis K.M.Shen. 425 Motai and Kitanaka (2004) identified four sesquiterpene coumarin derivatives from an 80% 426 aqueous methanol extract of the roots of F. fukanensis K.M.Shen: fukanemarin B (37), 427 fukanefuromarin E (38), fukanefuromarin F (39) and fukanefuromarin G (40) (Fig. 9). 17 (31), 428 Saradaferin ([decahydro-(3-α-hydroxy-4,4,10-trimethyl-8-methylene-9-naphthenyl)-α- 429 hydroxymethyl] ether of umbelliferone), a sesquiterpene coumarin, (41) (Fig. 10) was 430 separated from an OGR of F. assa-foetida L. (Bandyopadhyay et al., 2006). 431 Isofeterin (42), lehmannolol (43) and shinkianone (44) (Fig. 11) were identified from the 432 95% ethanol extract of the roots of F. teterrima Kar. & Kir. and F. sinkiangensis K. M. Shen 433 (Yang et al., 2006). 434 Three sesquiterpene derivatives, together with ten other compounds, were isolated from the 435 methanol extract from the roots of F. gummosa Boiss. Among those three compounds, 436 gumosin (45) is a coumarin derivative, and gumosides A and B (46 and 47, Fig. 12) are 437 coumarin glycosides (Iranshahi et al., 2010a). 438 The phytochemical characterization of the aqueous-ethanol (5:95, v/v) extract of the roots of 439 F. ferulaeoides (Steud.) Korov led to the separation of three sesquiterpenoid coumarins, 440 ferulin A-C (48-50) (Fig. 13) along with seven known sesquiterpenoid derivatives (Meng et 441 al., 2013a). 442 Recently, Bashir and colleagues (2014a) have identified two sesquiterpene coumarins, 443 fnarthexone (51) and fnarthexol (52) (Fig. 14), as well as three known coumarin derivatives 444 (umbelliferone, conferone and conferol) from the methanol extract of F. narthex Boiss. 445 obtained by using a maceration method. It is interesting to note that from the stereochemical 446 point of view, fnartexol (52) is the epimer at C-5′ of conferol, a natural compound also 447 identified in F. nartex Boiss. during the reported study. 448 Liu and collaborators (2015) separated 28 sesquiterpenoids from the ethanol extract of the 449 roots of F. ferulioides (Steud.) Korovin. Seven of these terpenoids were described for the first 450 time from the genus Ferula. Of these, three compounds (53-55) resulted to be sesquiterpene 451 coumarins (Fig. 15). 18 452 Dastan and co-workers (2012) separated two disesquiterpene coumarins from the n-hexane 453 extract of F. pseudalliacea Rech.f. roots (56-57) (Fig. 16), in addition to four known 454 sesquiterpene coumarins. 455 Li and colleagues (2015a) reported a sesquiterpene coumarin, namely sinkiangenorin D (58) 456 (Fig. 17), along with ten known sesquiterpene coumarins from the seeds of F. sinkiangensis 457 KM Shen. It is interesting to note that (58) is a sesquiterpenoid with a rare cycloheptene unit 458 in its structure. This structural feature might be subsequent to several rearrangements since 459 the common head-tail connenction between the isoprene units is no longer observable in its 460 structure. 461 In a similar study, sinkiangenorin F (59) and 8-O-acetyl sinkiangenorin F (60) (Fig. 18) were 462 characterized as the sesquiterpene coumarins in the ethanol extract of F. sinkiangensis KM 463 Shen (Li et al., 2015b). 464 Among the sixteen identified compounds in the chloroform extract of F. sinkiangensis K. M. 465 Shen, two compounds, (3′S, 8′R, 9′S, 10′R)-sinkianol A (61) and (3′R, 5′R, 10′R)-sinkianol B 466 (62) (Fig. 19) were identified for the first time (Xing et al., 2017). In addition, eleven known 467 compounds, 468 deacetylkellerin, farnesiferol A, farnesiferone A, gummosin, polyanthinin, (3'R,5'R,10'R)- 469 sinkianol B, galbanic acid, methyl galbanate and karatavicinol were reported for the first time 470 for this species. 471 472 5.1.4. Coumarinyl esters 473 In a related study, coumarin esters, 7-O-(4,8,12,16-tetrahydroxy-4,8,12,16-tetramethyl- 474 heptadecanoyl)-coumarin, ferulone A (63), and 7-O-(4-hydroxy-4,8,12-trimethyl-trideca- 475 7,11-dienoyl)-coumarin, ferulone B (64), (Fig. 20) were isolated from the non-polar (n- 476 hexane) fraction of extracts from the roots of F. orientalis L. (Razavi et al., 2016). These two 477 coumarin esters were isolated by a combination of vacuum liquid chromatography (VLC) and including ferukrin, (3'S,5'S,8'R,9'S,10'R)-kellerin, 19 (3'S,5'S,8'R,9'S,10'R)- 478 preparative thin-layer chromatographic (PTLC) and were characterized by means of 479 spectroscopic methods. 480 Razavi and Janani (2015) isolated a coumarinyl ester, ferulone C [7-O-(4,8,12-trihydroxy- 481 4,8,12-trimethyl-tridecanoyl)-chromen-2-one] (65) (Fig. 21) , from an n-hexane extract of the 482 roots of F. persica Wild. 483 484 5.1.4.1. Dihydrofuranocoumarinyl esters 485 Analysis of the dichloromethane soluble fraction of a methanolic extract from the roots of F. 486 lutea (Poir.) Maire afforded an inseparable mixture of two isomeric dihydrofuranocoumarin 487 esters with senecioic and angelic acids, respectively, (−)-5-hydroxyprantschimgin (66) and 488 (−)-5-hydroxydeltoin (67) (Fig. 22) (Ben Salem et al., 2013), together with eight other 489 compounds, (−)-prantschimgin, (−)-deltoin, psoralen, xanthotoxin, umbelliferone, caffeic 490 acid, β-sitosterol and stigmasterol. 491 492 5.2. Prenylated benzoic acid derivatives 493 Chen et al. (2000a) characterized the prenylated benzoic acid derivatives, kuhistanol A (68), 494 kuhistanol B (69), kuhistanol C (70), and kuhistanol D (71) (Fig. 23), in F. kuhistanica 495 Korovin, one of the most important medicinal plants of Uzbekistan. 496 Finally, this group introduced four further derivatives of farnesyl hydroxybenzoic acid, 497 kuhistanol E (72), kuhistanol F (73), kuhistanol G (74) and kuhistanol H (75) (Fig. 24) from 498 F. kuhistanica Korovin a medicinal plant growing wild in the Uzbekistan region (Chen et al., 499 2001). 500 501 5.3. Sesquiterpene chromones 502 In a complimentary work by Motai and Kitanaka (2005a), five sesquiterpene chromone 503 derivatives, fukanefurochromones (A-E) (76-80) (Fig. 25) from a water-methanol (20:80, 504 v/v) extract of F. fukanensis K.M.Shen roots were isolated. 20 505 Phytochemical analysis of the aqueous-ethanol (5:95, v/v) extract of the roots of F. 506 ferulaeoides (Steud.) Korov led to the separation of two sesquiterpene chromone derivatives, 507 ferulin D,E (81-82) (Fig. 26), along with seven known sesquiterpenoid derivatives (Meng et 508 al., 2013a). 509 510 5.4. Sesquiterpenes 511 Chen and colleagues (2000b) isolated five daucane-type sesquiterpenes, kuhistanicaol A (83), 512 kuhistanicaol B (84), kuhistanicaol C (85), kuhistanicaol D (86) and kuhistanicaol G (87) 513 (Fig. 27) from the methanol extract of the air-dried of stems and roots of F. kuhistanica 514 Korovin. 515 An eudesmanolide (88) and a carotene derivative (89) (Fig. 28) were isolated from a 516 methanol-methylene chloride (1:1) extract from the leaves of F. sinaica Boiss. (Ahmed et al., 517 2001). 518 An oxygenated sesquiterpenoid, (1S,4S,5R,6S,7S,10S)-5,10,11-cadinanetriol (90) (Fig. 29), 519 from a distinct Sardinian chemotype of F. communis L. was isolated from the acetone extract 520 (Appendino et al., 2001). 521 Diab and co-workers (2001) isolated 2,3-α-epoxyjaeschkeanadiol 5-benzoate (91) (Fig. 30) 522 from the methylene chloride extract of F. hermonis Boiss roots. 523 Two daucane esters, 14-(4'-hydroxybenzoyloxy)dauc-4,8-diene (92,) (Fig. 31) and 14-(4'- 524 hydroxy-3'-methoxybenzoyloxy)dauc-4,8-diene (93) (Fig. 31), were obtained from the n- 525 hexane fraction of F. hermonis Boiss (roots) (Galal et al., 2001) together with four other 526 diterpenes. 527 Found in the ethyl acetate extracts of the dried fruits of F. kuhistanica Korovin., were three 528 derivatives of daucane esters, namely kuhistanicaol H (94), kuhistanicaol I (95) and 529 kuhistanicaol J (96) (Fig. 32) (Tamemoto et al., 2001), along with nine other compounds. 21 530 Shikishima and collaborators (2002) characterized 17 sesquiterpenes in the ethyl acetate 531 extract from the dry roots of F. penninervis Regel and Schmalh. Fifteen of these were the 532 guaiane type (ferupennins A-O: 97-111) (Fig. 33), while the remaining two were of the 533 eudesmane type (112-113) (Fig. 33): 1α-hydroxy-2-oxo-5α,7β-11βH-eudesm-3-en-6α,12- 534 olide (112), and penninervin (113), respectively. Nine additional sesquiterpenes, already 535 known, were also identified. 536 Three daucane sesquiterpenes [(1R,4R)-4-hydroxydauca-7-ene-6-one (114), (1R,4R)-4- 537 hydroxydauca-7-ene-6,9-dione (115) and (1R,3S,8S)-3-ethoxy-8-angeloyloxydauca-4-en-9- 538 one (116), (Fig. 34) were characterized from the hexane extract prepared from the air dried 539 roots of F. hermonis Boiss (Lhuillier et al., 2005). 540 Sesquiterpene lactones 117-122 (Fig. 35) were isolated from the ethyl acetate-soluble fraction 541 obtained from the MeOH extract of F. varia (Schrenk) Trautv. roots (Suzuki et al., 2007) 542 together with five other sesquiterpenes, dehydrooopodin, oopodin, spathulenol, ferupennin L 543 and 8α-angeloyloxy-10β-hydroxyslov-3-en-6,12-olide. 544 The sesquiterpene derivatives (Fig. 36), 10-hydroxylancerodiol-6-anisate (123), 2,10- 545 diacetyl-8-hydroxyferutriol-6-anisate (124), 10-hydroxylancerodiol-6-benzoate (125), epoxy- 546 vesceritenol (126) and vesceritenone (127), along with six other compounds, were reported 547 among the components of the methylene chloride extract obtained from the aerial parts of F. 548 vesceritensis Coss. & Dur (Oughlissi-Dehak et al., 2008). 549 Alkhatib and colleagues (2008) identified two sesquiterpene esters, namely 6- 550 anthraniloyljaeschkeanadiol 551 hydroxybenzoyloxy)dauc-9-ene (elaeochytrin B) (129) (Fig. 37), from the dichlorometane 552 soluble fraction of the methanolic extract of the roots of F. elaeochytris Korovin. In the same 553 work, eight other compounds were also identified. These included 6-angeloyljaeschkeanadiol, 554 teferidin, ferutinin, (elaeochytrin A) (128) and 4β-hydroxy-6α-(p- 6-(p-hydroxybenzoyl)epoxyjaeschkeanadiol, 22 6-(p- 555 hydroxybenzoyl)lancerotriol, 5-caffeoylquinic 556 sandrosaponin IX. 557 From the dichloromethane extract of roots of F. badrakema Koso-Pol., badrakemonin (130) 558 (Fig. 38) (Iranshahi et al., 2009), a sesquiterpene, was isolated together with six known 559 sesquiterpene coumarins: mogoltacin, feselol, badrakemin acetate, ferocaulidin, conferone 560 and conferol acetate. 561 Sesquiterpene lactones, diversolides A (131), D (132), F (133) and G (134) (Fig. 39) were 562 isolated from the roots of F. diversivittata Regel & Schmalh. by Iranshahi et al. (2010b). 563 A sesquiterpene ester, tunetanin A (135), along with a sesquiterpene coumarin, 564 tunetacoumarin A (136) (Fig. 40), were reported from the dichloromethane-soluble fraction 565 of the methanol extract of F. tunetana Pomel ex Batt. roots (Jabrane et al., 2010). 566 Dall’Acqua and colleagues (2011) isolated three daucane sesquiterpenes (137-139) (Fig. 41) 567 from the dichloromethane fraction of an ultrasound assisted methanol extract of the roots of 568 F. communis subsp. Communis. Among these, 2α-Acetoxy-6α-p-methoxybenzoyl-10α- 569 hydroxy-jaeschkeanadiol 570 jaeschkeanadiol (138) were found to be the epimers of two other daucane sesquiterpenes, 2α- 571 acetoxy-6α-p-methoxybenzoyl-10β-hydroxy-jaeschkeanadiol 572 methoxybenzoyl-10β-hydroxy-jaeschkeanadiol, respectively, which had already been 573 identified in F. communis subsp. communis. The third characterized compound (139) was the 574 8,9-dihydro-8,14-dehydro-9-hydroxyferutinin, which had been obtained previously by a 575 semisynthetic approach but had never been isolated from a natural source. 576 Three daucane esters, out of a total of seventeen, (Fig. 42), namely feruhermonins A (4β- 577 hydroxy-6α-benzoyl-dauc-7-en-9-one) 578 benzoyl-dauc-9-ene) (141) and feruhermonins C (4β,9α-dihydroxy-6α-benzoyl-dauc-7-ene) 579 (142) were reported from the n-hexane-ethyl acetate (1:1) extract of the seeds of F. hermonis (137) and acid, 1,5-dicaffeoylquinic acid and 2α-hydroxy-6α-p-methoxybenzoyl-10β-acetoxy- (140), 23 feruhermonins and B 2α-acetoxy-6α-p- (4β,8β-dihydroxy-6α- 580 Boiss (Auzi et al., 2008). The epimer at C-8 of feruhermonins B (141), reported in Fig. 33 as 581 (141a), was isolated from the same species few years later by Ibraehim et al. (2012a). 582 From the water-soluble fraction of the methanol extract of F. varia (Schrenk) Trautv. roots, a 583 species widely used in the traditional medicine of Uzbekistan, seven other sesquiterpene 584 lactone glycosides with the eudesmane skeleton were isolated (143-149) (Fig. 43) (Kurimoto 585 et al., 2012b). To establish their absolute configurations the authors applied a modification of 586 Mosher’s method. 587 The analysis of a water extract of F. varia (Schrenk) Trautv roots resulted in the 588 characterization of eight natural compounds of which five (150-154), two (155-156) and one 589 (157) (Fig. 44) are, respectively of the eudesmane, guaiane and germacrene lactone glucoside 590 types (Kurimoto et al., 2012a). 591 Liu and collaborators (2015) separated 28 sesquiterpenoids from an ethanol extract of the 592 roots of F. ferulioides (Steud.) Korovin, of which seven were described for the first time from 593 the genus Ferula (Fig. 45). Four of these compounds (158-161) showed a structure in which a 594 resacetophenone unit is linked to a linear (158, 159) or rearranged sesquiterpene moiety to 595 form a dihydrofurane structure (160, 161). 596 597 5.5. Sulfur containing metabolites 598 From the chloroform extract of the aerial parts of F. behboudiana Rech. f. Esfand, four 599 polysulphane 600 enyl]disulphane (162), 1-sec-butyl-2-[(Z)-3-(methylthio)prop-1-enyl] disulphane (163), 1- 601 [(E)-3-(methylthio)prop-1-enyl)-2-(1-(methylthio)propyl] disulphane (164) and 1-[(Z)-3- 602 (methylthio)prop-1-enyl)-2-(1-(methylthio)propyl] disulphane (165) (Fig. 46) were reported 603 (Yousefi et al. (2010). 604 More recently, five novel sulfur-containing compounds, latisulfide A (166), latisulfide B 605 (167), latisulfide C (168), latisulfide D (169) and latisulfide E (170) (Fig. 47), have been related compounds, namely 24 1-sec-butyl-2-[(E)-3-(methylthio)prop-1- 606 isolated from the dichloromethane extract of F. latisecta Rech.f. & Aellen (Soltani et al., 607 2018). 608 Sulfur-containing heterocylcic compounds, foetithiophene C (171), foetithiophene D (172), 609 foetithiophene E (173) and foetithiophene F (174) (Fig. 48), were also obtained from the 610 roots of F. foetida Regel (petroleum ether extract) (Chitsazian-Yazdi et al., 2015). 611 612 5.6. Miscellaneous 613 Abd El-Razek (2007) isolated a caffeic acid cinnamyl ester, (2E)-3,4-dimethoxycinnamyl-3- 614 (3,4-diacetoxyphenyl) acrylate (175), from the n-hexane soluble fraction obtained from 615 methanol extract of the OGR of F. assa-foetida L. (Fig. 49). 616 Meng and collaborators (2013b) isolated eight sesquiterpenoids, ferulaeone A-H (176-183) 617 (Fig. 50) from F. ferulaeoides (Steud.) Korov. The proposed structures assignment were 618 based not only on experimental spectroscopic data, but also on biosynthetic pathway, which 619 might imply the condensation between the appropriate Coenzyme-A activated C6–C3 620 derivative and farnesyl pyrophosphate. 621 Ibraheim and colleagues (2012b), isolated a saponin (sandrosaponin XI) (184) (Fig. 51) from 622 the n-butanol extract of the root of F. hermonis Boiss. Sandrosaponin XI has an oleanane 623 pentacyclic triterpene skeleton. The complete structure of the saponin (184) was shown to be 624 the methyl ester of 3β-O-β-D-glucopyranosyl-(1→2)-β-D-galactopyranosyl-(1→2)-β-D- 625 glucuronopyranosyl-oleanolic acid-28-O-β-D-glucopyranoside. 626 The steroidal esters, sinkiangenorin A (185) and sinkiangenorin B (186) and the organic acid 627 glycoside sinkiangenorin C (187) (Fig. 52) were isolated from the ethanol extract from the 628 seeds of F. sinkiangensis KM by Shen Li and co-workers (2014). Four known lignin-related 629 compounds were also identified during the same study. 630 Screening of a methanol-water (7:3) extract of the flowers of F. lutea (Poir.) Maire yielded 631 ferunide, (E)-5-ethylidenefuran-2(5H)-one-5-O-β-D-glucopyranoside (188), in addition to 425 632 hydroxy-3-methylbut-2-enoic acid (189) (Fig. 53) (Znati et al., 2014). This extract also 633 contained nine known compounds, which could be partitioned between ethyl acetate and n- 634 butanol. Of these, six compounds, 5-O-caffeoylquinic acid, methyl caffeate, methyl 3,5-O- 635 dicaffeoylquinate, 636 rhamnopyranosyl(1→6)-β-D-glucopyranoside, narcissin, and (_)-marmesin, even if quite 637 common plant metabolites, were identified for the first time in the Ferula genus. 638 The phytochemical patterns recognized in Ferula species are varied. These include different 639 classes of natural products, i.e. coumarins, sesquiterpenes, phenylpropanoids, saponins, 640 chromones, sulfur-containing compounds and steroids. Among these phytoconstituents, the 641 coumarins, and in particular the furanocoumarins (linear and/or angular), very often esterified 642 with short chain organic acids such as acetic, angelic and/or senecioic acids, are characteristic 643 constituents of several species of the Apiaceae family, for instance, Coristospermum 644 cuneifolium (Guss.) Bertol. (Venditti et al., 2016), Ligusticum pyrenaicum W.D.J.Koch 645 (Bohlmann and Grenz, 1969), Ferulopsis hystrix (Bunge ex Ledeb.) M. Pimen. (Shulˈts et al., 646 2012) and Ferulago angulata (Schltdl.) Boiss (Razavi et al., 2015), among the others. In this 647 context, the peculiar spirobicoumarins are noteworthy to the best of our knowledge, since 648 they have been recognized so far only in the Apiaceae family, i.e. in Pleurospermum 649 rivulorum (Diels) M. Hiroe (Taniguchi et al., 1998). The sesquiterpenoids are also considered 650 as chemotaxonomic markers in the Apiaceae, and the genus Ferula showed a widespread 651 presence of compounds of several families of sesquiterpene lactones, including derivatives 652 containing the cadinane, daucane, guaiane, eudesmane and carotane backbones. All these 653 compounds are useful taxonomic markers within the genus, but they also provide evidence of 654 the systematic proximity among various genera in the Apiaceae family itself. The main 655 metabolic feature, which may be observed by considering the wide list of compounds and 656 chemical structures reported in this review, is the presence of a huge number of metabolites 3,5-O-dicaffeoylquinic 26 acid, isorhamnetin-3-O-α-L- 657 of mixed biosynthetic origin, such as hemi- mono- and sesquiterpene coumarins, 658 sesquiterpene chromones, sesquiterpene polyketides, furochromones and prenylated benzoic 659 acid derivatives. Concerning the sesquiterpene coumarins and the sesquiterpene chromones, 660 the species of the Ferula genus resulted to be very efficient producer of these rare 661 phytoconstituents. The occurrence of these secondary metabolites seems to be restricted to a 662 few species within the Apiaceae, the Asteraceae and the Rutaceae families (Gliszczyńska and 663 Brodelius, 2012). Last but not the least, the sulfur-containing secondary metabolites, present 664 as different derivatives such as thiophenes, disulfanes and trisulfanes, found in both the 665 volatile fraction and organic solvents extracts, are an additional distinctive chemical trait of 666 the Ferula species which confer the characteristic smell to several species of the genus. 667 The presence of a wide variety of secondary metabolites of mixed biogenetic origin (i.e. 668 hemiterpene-coumarins (Fig. 4), monoterpene-coumarins (Fig. 5), sesquiterpene-coumarins 669 (Figs. 6-19), sesquiterpene polyketides (Fig. 45) and sesquiterpene-chromones (Figs. 25-26) 670 have a relevance also from the medicinal chemistry standpoint. In fact, in recent years, the 671 approach consisting in the fusion (by the use of a suitable linking group or exploiting directly 672 the functionalizations already present on the structures to be connected) of two biologically 673 active structural moieties has been largely explored for different purposes. For instance, with 674 the scope of specific organ/tissue delivery or to enhance a specific bioactivity taking 675 advantage from the synergistic properties of molecules with different structures or with 676 different cellular targets which are involved in the development of a specific pathology. 677 Currently, it is unknown why most of the species belonging to this genus showed this 678 metabolic behavior. There could be many valid hypotheses, even different one from the other. 679 One might be, obviously, the fusion of two molecules with different biological activity in one 680 derivative so to have a compound effective toward different biological targets. Another might 681 have its rationale in the physiological field i.e. the fusion of two molecules in one will reduce 27 682 the osmotic pressure by reducing the number of particles present in the cellular environment. 683 In any case, it remains an argument that deserves further investigation with dedicated studies. 684 However, it is a case that clearly represents how much Nature has already used some of the 685 chemical-pharmaceutical approaches that we believe to be innovative and, therefore, 686 emphasizes the importance of phytochemical studies that contribute to revealing chemical 687 aspects and physiological/ecological functions of secondary (specialized) metabolites and can 688 offer interesting approaches for use in medicinal and pharmaceutical chemistry. 689 To date, there are only a limited number of Ferula species already subjected to the systematic 690 phytochemical analysis. Therefore, it is obvious that in the future, several other new 691 compounds might be recognized as phytoconstituents of the Ferula genus and new biological 692 activities may be explored. This is particularly probable for the endemic entities since it has 693 been largely confirmed that the endemism is a condition which may promote the metabolic 694 diversity (Bianco et al., 2016) in respect to species with a more wide area of distribution. 695 Considering the chemical structures of the majority of the Ferula secondary metabolites and 696 the proposed biogenesis (Su et al., 2000; Meng et al., 2013b), it is evident that the biogenetic 697 pathways involving terpenoids and phenylpropanoids are particularly active. These are also 698 interacting among them to synthesize compounds with mixed biogenetic origin, thus it is 699 most probable that new metabolites possibly isolated in future studies might exhibit these 700 structural features. 701 702 7. The bioactivities of diverse characterized compounds from the genus Ferula 703 There have been numerous papers dealing with the biological and medicinal properties of 704 some species of the genus Ferula. These important characteristics are discussed in the 705 following subsections. 28 706 707 7.1. Anti-HIV activity 708 Some of the known compounds isolated form Ferula spp., namely oxypeucedanin hydrate, 709 heraclenol, oxypeucedanin, heraclenin, pranferol, pabulenol, osthol and xanthotoxin, were 710 tested for their anti-HIV activity by Zhou and collaborators (2000). These compounds 711 resulted effective with IC50 ranging from 11.7 to > 100 μg/mL and EC50 ranging from < 0.10 712 to 33.3 μg/mL, in comparison to AZT as positive control (IC50 and EC50, 500 and 0.032 713 μg/mL, respectively). Several of these components, namely heraclenol, oxypeucedanin, 714 heraclenin and osthol, showed a Therapeutic Index (TI) > 5, thus denoting significant 715 activity. Interestingly, pabulenol showed a TI > 1000. Therapeutic indices > 1000 are 716 characteristic values of most of the drugs currently used in therapy. Based on this data, 717 pabulenol could be an excellent drug candidate having a little intrinsic toxicity. 718 Unfortunately, in this case, it is not possible to estimate the real quantity of these constituents 719 in the plant materials since in the experimental section are reported unlikely quantities of 720 plant material (500 g) compared to the volume of extraction solvent (50 l x 3) and the amount 721 of isolated components, some of which in gram scale. Therefore, the extracted plant material 722 was likely much greater than the reported value. 723 724 7.2. Inhibitory activity on cytokine production 725 Chen et al. (2000a) evaluated the inhibitory activity on cytokine production LPS-activated 726 human peripheral mononuclear cells. In this study, kuhistanol D (71) showed significant 727 immunosuppressive activity by inhibiting the production (%) of several cytokines at 728 concentrations of 3 μg/mL (IL-4; 70%, IL-2: 77%, IFN-γ: 62%), although the other 729 compounds showed no significant inhibitory effects even at higher concentration (10 μg/mL). 730 This result may suggest that the presence of the bicyclic chromane moiety in compound (71) 731 is necessary to exert the immunosuppressive activity. A quantity of 113.5 mg of (71) was 29 732 obtained from 2.25 Kg of plant materials, thus accounting for the 0.005% w/w and so 733 resulting to be a minor component. 734 735 7.3. Inhibitory activity on NO production 736 The inhibitory activity on NO production of (76-79) was tested in a murine macrophage-like 737 cell system induced by LPS/INF-γ (Motai and Kitanaka, 2005a). In this study, compound 738 (80) was not isolated in a sufficient amount (1.5 mg) to be further tested. However, 739 compounds (76-79) were effective in inhibiting NO production with IC50 values of 9.8 μg/mL 740 (25 μM), 8.9 μg/mL (23 μM), 12 μg/mL (29 μM) and 9.5 μg/mL (24 μM), respectively, and 741 showed no cytotoxicity at the tested concentrations. Among these sesquiterpene chromones, 742 (79) showed a dose dependent inhibition of iNOS mRNA expression. Furthermore, the 743 compound (79) showed a moderate inhibitory activity in LPS-induced NO production in a 744 murine macrophage-like cells system (RAW264.7) with an IC50 value of 55 μM (Abd El- 745 Razek, 2007). From 5.9 Kg of raw plant materials were recovered 23.8 mg of (76), 5.5 mg of 746 (77), 19.6 mg of (78) and 7.9 mg of (79), accounting for 0.0004, 0.00009, 0.00033 and 747 0.00013 % (w/w), respectively, resulting so minor components. 748 749 7.4. The inhibitory on Epstein-Barr virus early antigen (EBV-EA) activation 750 The inhibitory potentialities on Epstein-Barr virus early antigen (EBV-EA) activation 751 induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) were tested in vivo in a mouse 752 model (Iranshahi et al., 2010b). All the new sesquiterpene lactones (45-47) resulted to be 753 active (IC50 ranging from 8.7 and 10.7 nM) with inhibitor percentages comprised between 754 92.5 ± 0.6 and 89.2 ± 0.9 when applied at a concentration of 32 nM and between 63.6 ± 1.3 755 and 68.3 ± 1.6 when applied ad 16 nM, in respect to the positive control experiments. The 756 compounds (45-47) accounted for the 0.0128, 0.051 and 0.042 % (w/w) in respect to the 757 extracted plant materials, resulting therefore minor components. 30 758 759 7.5. Inhibitory against Plasmodium falciparum 760 It has been reported that sanandajin (56) and kamolonol acetate (57) showed moderate 761 activity against Plasmodium falciparum strain K1, with IC50 values of 2.6 and 16 μM, 762 respectively (Dastan et al., 2012). Compounds (56) and (57) are present in a percentage of 763 0.00134 and 0.00336 % (w/w), respectively, in the raw plant materials. 764 765 7.6. Antineuroinflammatory potential in LPS-activated BV-2 microglial cells 766 Xing and colleagues (2017), tested the isolated compound (61), together with several known 767 metabolites, for the antineuroinflammatory potential in LPS-activated BV-2 microglial cells. 768 Compound (61) showed a moderate inhibition of NO production (IC50 > 50 µ M), whereas the 769 most effective, and also the major constituent, resulted to be the known (3′S,5′S,8′R,9′S,10′R)- 770 kellerin, which significantly inhibited the mRNA expression of several inflammatory factors 771 (TNF-α, IL-6, IL-1β, COX-2) at concentration between 1 and 10 µM. Conversely, the other 772 new sesquiterpene coumarin (62) was not subjected to the bioactivity test, even if isolated in 773 sufficient amount (42.1 mg). The compounds (61), (62) and the known (3′S,5′S,8′R,9′S,10′R)- 774 kellerin accounted for the 0.0036, 0.0087 and 1.5 % (w/w), respectively, of the whole 775 composition of the analyzed gum resin. Considering the relative abundance of 776 (3′S,5′S,8′R,9′S,10′R)-kellerin and its pronounced activity at µmolar concentrations it is quite 777 probable that the biological activity observable in the crude gum resin might be attributable to 778 this single compound. In addition, due to the quite high amount of (3′S,5′S,8′R,9′S,10′R)- 779 kellerin in the raw materials also the extractive approach to obtain the pure compound is 780 applicable. 781 782 7.7. Cytotoxicity 783 The sesquiterpene lactones (117-122) from the ethyl acetate-soluble fraction obtained from a 784 MeOH extract of F. varia (Schrenk) Trautv. roots, along with some known sesquiterpenes 31 785 (dehydrooopodin, oopodin, spathulenol, ferupennin L and 8α-angeloyloxy-10β-hydroxyslov- 786 3-en-6,12-olide), were tested for their cytotoxicity against multidrug-resistant cancer cells, 787 KB-C2 (colchicine-resistant KB) and K562/Adr (doxorubicin-resistant K562) (Suzuki et al., 788 2007). This study revealed a significant selective cytotoxicity for the compound (120) (IC50 789 value of 15.7 µg/mL) against KB-C2. Differently, compounds (117), (119) and (121) showed 790 enhanced cytotoxicity (IC50 values ranging from 25.4 to 67.8 µg/mL) in the presence of non- 791 toxic concentrations of colchicine (2.5 µM) against the same cell line showing so an 792 interesting synergistic activity which may suggest a possible use in combined therapy. 793 Unfortunately, these new compounds accounted for very low percentages of plant material 794 composition, 0.00014, 0.00078, 0.00078, 0.0018, 0.00028 and 0.00064% (w/w), respectively 795 for (117-122). Therefore, estractive procedure could be not adequate to obtain sufficient 796 amount of these compounds, instead a synthetic approach might be most useful and it could 797 likely be an interesting further challenge for synthetic chemistry. 798 In a different study, the new compounds (135) a sesquiterpene ester and (136), a 799 sesquiterpene coumarins, were tested for their cytotoxicity towards two human colon cancer 800 cell lines, HT-29 and HCT-116, but were found to be not effective (Jabrane et al., 2010) 801 against these cancer cell lines, showing IC50 > 100 μΜ. Conversely, the known coladin, 802 coladonin and 13-hydroxyfeselol, also isolated in the same study and tested toward the same 803 cell lines, showed weak activity with IC50 value of 3.7 ± 1.5, 15.1 ± 1.5, 34.1 ± 2.3 μΜ, 804 respectively, against HTC-116 and 5.4 ± 1.2, 13.3 ± 2.3, 35.4 ± 4.0 μΜ, respectively, against 805 HT-29 cell line. Paclitaxel was used as positive control. The most active compounds, coladin 806 and coladonin, are sesquiterpene coumarins with a structure related to those of (136). The 807 main structural difference of the active compounds is the presence of a double bond between 808 C-8 and C-12, while in (136) C-8 is a quaternary carbon functionalized with a methyl and 809 hydroxyl group in geminal configuration, and this may suggest that the unsaturation in this 32 810 position may enhance the cytotoxic activity. A second structural feature which, on the 811 contrary, exert a lowering of the effectiveness is the presence of the ester function. In fact, 812 coladonin, the less active, has an acetyloxy function in C-3 instead of the alcoholic function 813 present in coladin at the same position. Moreover, the position and the nature of the acidic 814 moiety of the ester functionalization might have a role in lowering the effectiveness of the 815 sesquiterpene coumarins as observed in the derivative (136), bringing an angeloyloxy 816 function in C-13, which showed no efficacy. The new compound (135) accounted for 817 0.00055% and compound (136) for 0.00066% (w/w) of raw plant materials, thus representing 818 minor components. On the contrary the more active components, coladin and coladonin, 819 accounted for 0.0741 and 0.0222% (w/w), respectively, of the whole raw materials 820 composition. Considering the amount of coladin in the plant materials and its low value of 821 IC50 this could be one of the few compounds of which the extraction from the natural source 822 for medicinal purposes might be justifiable also from the economical standpoint. 823 In a similar study by Meng and colleagues (2013a), ferulins B and C (49 and 50), showed a 824 moderate level of cytotoxicity against HepG2 (IC50 = 89 ± 2 and 76 ± 2 μΜ, respectively), 825 and C6 (IC50 = 21 ± 1 and 36 ± 1 μΜ, respectively) cancer cell lines but resulted inactive 826 against the MCF-7 cell line. Also in this case, these two compounds (49 and 50) resulted to 827 be minor components of the raw plant materials, accounting for the 0.001055 and 0.000702% 828 (w/w), respectively. 829 Similar results were obtained also for the new sesquiterpenoids ferulaeone F-H (181, 182 and 830 183) which exhibited a moderate cytotoxicity against HepG2 (IC50 of 86, 87 and 82 μΜ, 831 respectively), MCF-7 (IC50 of 87, 92 and 82 μΜ, respectively), and C6 (IC50 of 65, 59 and 66 832 μΜ, respectively) cancer cell lines (Meng et al., 2013b). Among these terpenoids, the 833 compound (181) resulted to have the higher percentage in the composition of raw materials 834 with the 0.0244 % (while the other accounted for 0.001 and 0.0007% (w/w)). It should be 33 835 also underlined that the relative high value of IC50 recorded in the bioactivity test does not 836 allow classifying it as a compound with sufficiently high activity, so its possible practical use 837 is very unlikely. 838 In a different work, both of the newly characterized compounds, a glucosidic furanone 839 derivative (187) and the γ-hydroxy-senecioic acid (188) showed no cytotoxicity toward the 840 tested cell lines involving human colon carcinoma, HCT-116, human ovary carcinoma, 841 IGROV-1 and human ovary adenocarcinoma, OVCAR-3, in MTT assays (Znati et al., 2014). 842 Finally, latisulfides A-E (166-170) were tested for their in vitro cytotoxic activity against 843 human cancer cell lines including HeLa, HCT116, A2780 and A549 (Soltani et al., 2018). In 844 this relation, the majority of the characterized compounds showed IC50 values > 100 μM and 845 only latisulfide C (168) exerted a moderate cytotoxicity with IC50 values of 49, 65 and 87 μM 846 against HeLa, HCT116 and A2780 cell lines, respectively, but resulted less effective toward 847 A549 cell line. The compound (168) accounted for the 0.0012% of raw materials 848 composition. Also in this case the the relative high value of IC50 and the relative low 849 abundance in the plant materials, suggest a poor practical applicability of this compound. 850 851 7.8. Antibacterial and antimicrobial activity 852 Galal and collaborators (2001) demonstrated that 14-(4'-hydroxybenzoyloxy)dauc-4,8-diene 853 (92), isolated along with jaeschkeanadiol p-hydroxybenzoate, exhibited antibacterial activity 854 toward Staphylococcus aureus (SA) with IC50 values of 1.5 and 3.5 μg/mL, respectively, and 855 methicillin-resistant S. aureus (MRSA) having IC50 values of 2.0 and 4.0 μg/mL, 856 respectively. Tetracycline was used as positive control. The daucane derivative (92) 857 accounted for 0.025% (w/w) of plant materials, while no data about the relative abundance of 858 jaeschkeanadiol p-hydroxybenzoate have been reported in the original article. The easy 859 isolation procedure of (92) from the plant materials plays in favor to the possibility of 34 860 obtaining this compound in pure form and the low values of IC50 against MRSA and SA 861 make it a possible candidate as an antibacterial drug. 862 Actually, jaeschkeanadiol p-hydroxybenzoate, together with other known compounds, 863 namely jaeschkeanadiol vanillate, kuhistanol D and kuhistanol A, were screened for the 864 antimicrobical activity also in a different study by Tamemoto et al. (2001). In particular, 865 these compounds were tested against eight Gram-positive and Gram-negative bacterial 866 species, including methicillin-sensitive and methicillin-resistant S. aureus (MSSA, MRSA). 867 The two jaeschkeanadiol derivatives, exhibited significant activity (MIC comprised between 868 8 and 31 μg/mL) against the Gram-positive S. aureus (MSSA, MRSA), S. epidermidis, E. 869 faecalis, and B. subtilis with efficacies comparable to those of the standard antibiotics, 870 ampicillin (MIC 0.125-2 μg/mL) and chloramphenicol (MIC 2-16 μg/mL). Unfortunately, 871 these compounds were isolated in the order of 2.3 and 2.5 mg, respectively, for 872 jaeschkeanadiol p-hydroxybenzoate and jaeschkeanadiol vanillate, from 600 g of plant 873 materials, thus resulting minor components. 874 The antibacterial activities of the isolated compounds (53-55 and 158-161) were assayed 875 against a panel of bacteria including multidrug-resistant (MDR) and methicillin-resistant 876 Staphylococcus aureus (MRSA), and mostly exhibited weak activities (Liu et al., 2015). The 877 best result obtained in this study was observed for the new compound (158) (yield 0.015% 878 (w/w)) against the multidrug-resistant S. aureus (strain SA-1199B) with a MIC value of 16 879 mg/L, (37 mM) resulting more effective in respect to the antibiotic norfloxacin 32 mg/L, (100 880 mM) used as positive control. 881 Foetithiophene F (174) (yield 0.006% w/w) showed a low antifungal activity against Candida 882 albicans with an MIC value of 200 µg/mL, and its highest antimicrobial activity was 883 observed against the Gram-positive bacteria B. cereus with a MIC value of 50 µg/mL 884 (Chitsazian-Yazdi et al., 2015). The other foetithiophenes C-E (171-173) were either inactive 35 885 or showed higher MIC values, i.e., ranging from 100 to 400 µg/mL. Even if these compounds 886 showed a certain activity it was not so striking that it could justify a possible use. 887 888 7.9. Anti-inflammatory activity 889 The anti-inflammatory activity of sesquiterpene coumarins (31-36) was evaluated (Motai et 890 al., 2004). Almost all of them inhibited the inducible NO-synthase expression more 891 efficiently than quercetin as a positive control (only compound 31 resulted to be less active) 892 in both lipopolysaccharide (LPS) and recombinant mouse interferon-γ-induced inflammation 893 in a murine macrophage-like cell line (RAW 264.7). The recorded IC50 comprised between 894 8.9 and 19.5 μM suggests a great potential as an anti-inflammatory agents. The structural 895 features necessary to exert the observed activity were reconducted to the presence of the 896 following functionalization: α,β-unsaturated ketones; position and configuration of the double 897 bond in the sesquiterpene unit (Z configuration enhances the inhibitory activity). 898 Furthermore, these compounds showed no cytotoxicity in MTT assay. Unfortunately, they 899 accounted for a very little quantity of the raw plant materials (5.9 kg) being isolated in 900 amounts from 4.7 to 40 mg. 901 Other active anti-inflammatory constituents of the Ferula spp. was the newly characterized 902 glucosidic furanone derivative (188) which showed only a moderate inhibitory activity (17 ± 903 1% at 80 µmol/L) but exerted toward a different enzymatic target, the 5-lipoxygenase an 904 enzyme involved in the eicosanoids metabolism catalizing the production of other 905 inflammatory mediators than prostaglandins, such as leukotrienes and lipoxins (Znati et al., 906 2014). In addition, in this case (188) accounted for a very little percentage of raw plant 907 materials (0.00034% w/w) thus resulting a minor components not easily useful as active 908 compound. 909 910 7.10. Inhibitory behavior of transcription-activating factors for iNOS mRNA 36 911 It has been shown that the four new sesquiterpene coumarins (37-40) inhibited the 912 transcription-activating factors for iNOS mRNA in a dose-dependent manner with IC50 values 913 of 30 ± 2 µM; IC50 = 29 ± 1 µM; IC50 = 31 ± 1 µM; IC50 = 27 ± 2 µM, respectively (Motai 914 and Kitanaka, 2004). The cytotoxic potential of these compounds, tested by the MTT assay, 915 was not significant (3-100 mM), as well. Unfortunately, they were obtained in mg amount 916 (ranging from 13.7 to 23.0) from 5.9 kg of plant materials, thus resulting to be minor 917 components. 918 919 7.11. Antiprolifertive/anticancer activity 920 The antiprolifertive activity of the compounds (114-116) in the estrogen-dependent MCF-7 921 cells was evaluated with contrasting results: Compound (114) and (116) exhibited 922 proliferative activity, whereas (115) showed an antiproliferative action (Lhuillier et al., 923 2005). Genistein and β-estradiol were used as positive controls. Also in this case the isolated 924 amounts (10.6, 7.5 and 5.6 mg) indicate that these are minor components in plant materials 925 (5.4 kg). 926 On the other hand, Alkhatib et al. (2008) screened the antiproliferative activities of the 927 isolated compounds elaeochytrins A and B (128 and 129, respectively) on K562R human 928 chronic myeloid leukaemia (imatinib-resistant) and DA1-3b/M2BCR-ABL mouse leukemia 929 (dasatinib-resistant) cell lines. According to the findings of this is study, of the two new 930 compounds elaeochytrin A (128) was the more active compound on both cell lines (IC50 931 values 12 and 8 μM, respectively). It was also active against non-resistant human 932 promyelocytic leukemia cells (HL60), having an IC50 value of 13 μM. However, the toxicity 933 toward normal peripheral blood mononuclear cells was not observed at concentrations up to 934 100 μM, while elaeochytrin B (129) showed a low activity (IC50 = 65.0 μM) against DA1- 935 3b/M2BCR-ABL and resulted inactive toward K562R. Compound (128) accounted for 0.28% 37 936 w/w on raw materials and therefore resulted to be contained in a sufficient amoun in the plant 937 materials to justify a practical use i.e. for extractive purposes of the active compound. 938 In addition, Iranshahi et al. (2010a), determined the antiproliferative activity of the isolates 939 against a small panel of cancer cell lines [M14 (human melanoma), MCF-7 (breast 940 carcinoma), T98G (glioblastoma), A549 (lung carcinoma), Saos-2 (osteosarcoma), FRO 941 (thyroid carcinoma), and U937 (leukemic monocyte lymphoma)] using the MTT assay. 942 However, only the already known feselol was found to be active against one cell line (U937), 943 with an IC50 value of 8 μM. Unfortunately, the newly characterized compounds (45-47) were 944 found to be inactive. 945 The antiproliferative activity of the isolated compounds (137-139) was tested against several 946 human tumor cell lines. The new compounds showed varying activities: 2α-acetoxy-6α-p- 947 methoxybenzoyl-10α-hydroxy-jaeschkeanadiol (137) showed very little activity toward 948 A549, HeLa and K562, with IC50 values > 100, 52 ± 2 and 70 ± 6 μM, respectively. 949 However, this compound was more active against HL-60, Jurkat, RS 4;11 and SEM having 950 IC50 values 15 ± 5, 9 ± 4, 27 ± 4 and 27 ± 2 μM, respectively. Furthermore, 2α-hydroxy-6α-p- 951 methoxybenzoyl-10β-acetoxy-jaeschkeanadiol (138) showed promising activity against HL- 952 60 and Jurkat (IC50 values of 24 ± 4 and 34 ± 6 μM, respectively) while for the other cell 953 lines only moderate to little activity was observed with IC50 values ranging from 70 - >100 954 μM. Finally, 8,9-dihydro-8,14-dehydro-9-hydroxyferutinin (139) displayed the best 955 cytotoxicity only against RS 4;11 and SEM cell lines, specifically with IC50 values of 29 ± 4 956 and 35 ± 2 μM, respectively, and exhibited low or moderate activity against the other tested 957 cell lines, with IC50 values ranging from 43 - >100 μM (Dall’Acqua et al, 2011). These active 958 compounds (137-139) resulted present in the analyzed raw plant materials (450 g) with the 959 following amounts, respectively: 21.4, 8.2 and 13.2 mg. 38 960 An inseparable mixture of dihydrofuranocoumarin isomers (66, 67) exerted antiproliferative 961 activity against HT-29 and HCT 116 cell lines, with IC50 values of 0.290.05 and 1.6 ± 0.6 962 μM, respectively (Ben Salem et al., 2013). Unfortunately, in this report no indication about 963 the isolated quantities were provided, therefore it is not possible to estimate their abundance 964 in the plant materials and the potentiality for an effective practical application. 965 Li and colleagues (2014), tested the isolated compounds for their potential antiproliferative 966 activity. Sinkiangenorin C (187) was found to be cytotoxic against the AGS human cancer 967 cell line, with an IC50 value of 37 μM, while sinkiangenorins A and B resulted inactive 968 against all the tested cell lines. Compound (187) was obtained in 9 mg yield from 4.2 kg of 969 plant materials. Therefore, considering that it is a minor component and showed not 970 extremely high bioactivity, its practical use is quite impossible. 971 In a related study, the two new compounds (59, 60) were tested for their antiproliferative 972 activities against K562, HeLa, and AGS human cancer cell lines. Compound (59) showed a 973 moderate cytotoxic activity against the AGS cell line, with an IC50 value of 27 ± 1 μM, while 974 (60) was less effective (IC50 = 63 ± 3 μM), in comparison with the standard drug taxol (IC50 = 975 3.5 ± 0.04 μM) (Li et al., 2015b). Conversely, cell lines K562 and HeLa did not show any 976 appreciable sensitivity towards these compounds (59, 60). Furtermore, in this case these 977 compounds resulted to be only minor components being isolated in 16.0 and 9.0 mg, 978 respectively, from 4.2 kg of raw plant materials. 979 Lastly, the cytotoxic tests of the characterized sulfur containing foetithiophenes C-F (171- 980 173) implied that none of the identified compounds showed cytotoxicity (IC50 > 100 μM) 981 against MCF-7 and K562 cell lines (Chitsazian-Yazdi et al., 2015). 982 Accordingly to the data reported by Li and collaborators (2015a), the compound 983 sinkiangenorin D (58) showed promising anticancer activity in AGS with an IC50 value of 20 984 ± 1 μM, while resulted moderately active against HeLa and K562 human cancer cell lines, 39 985 with IC50values of 81 ± 1 and 105 ± 1 μM, respectively. A quantity of 13.0 mg of (58) was 986 obtained from 4.2 kg of plant materials together with ten known metabolites, also present in 987 mg scale. 988 989 7.12. Antioxidant activity 990 The antioxidant potential of a mixture of identified compounds (66, 67) was assessed by 991 some standard assays including DPPH·, ABTS·+, singlet oxygen (1O2) and hydrogen peroxide 992 (H2O2), which resulted in IC50 values of 19, 13, 7.6, and 4.8 μM, respectively (Ben Salem et 993 al., 2013). They showed to be less active in respect to BHT, used as positive control, in both 994 DPPH· and ABTS·+ tests (IC50 = 9.02 ± 0.49 μg/mL and 6.85 ± 0.11 μg/mL, respectively). 995 Conversely, they showed an effectiveness comparable to BHT (IC50 = 7.26 ± 0.13 μg/mL) 996 against singlet oxygen and resulted more active than the positive control (IC50 = 6.38 ± 0.04 997 μg/mL) in hydrogen peroxide assay. The ability to act as antioxidant compounds was 998 attributed to the presence of the OH phenolic function in C-5 of both compounds. 999 Unfortunately, in this report no indication about the isolated quantities were provided, 1000 therefore it is not possible to estimate their abundance in the plant materials and the 1001 potentiality for an effective application. 1002 The new compounds (63 and 64), ferulone A and B, respectively, were tested for their 1003 antioxidant potential in DPPH· assay but showed only a low level of free-radical-scavenging 1004 activity with values of 0.25 and 0.56 mg/mL, respectively, in comparison to that observed for 1005 the positive control (quercetin, 0.004 mg/mL) (Razavi et al., 2016). Their amounts accounted 1006 for 0.0081 and 0.0089% w/w of plant materials. 1007 1008 7.13. The antileishmanial activity 1009 The antileishmanial activities of extract, fractions and pure compounds involving fnarthexone 1010 (51) and fnarthexol (52) together with three known natural compounds, namely 40 1011 umbelliferone, conferone and conferol have been tested (Bashir et al., 2014a). As shown in 1012 this work, the new compounds (51 and 52) showed only moderate activity with IC50 values of 1013 43.77 ± 0.56 and 46.81 ± 0.81 μg/mL, respectively. The most potent antileishmanial activity 1014 observed in this study was attributed to conferol with an IC50 value of 11.51 ± 0.09 μg/mL. It 1015 is interesting to note the different bioactivity level recorded for the two epimers fnartexol (52) 1016 and conferol, because the only structural difference between these two compounds stands in 1017 the opposite configuration at C-5′. This may obviously suggest an important influence of the 1018 stereochemistry at this site (this imply a different configuration of the fused rings in the cis- 1019 form) for what concerns the enhancing of the antileishmanial activity of sesquiterpene 1020 coumarins and could be an useful structural feature in projecting new synthetic active 1021 derivatives. The new fnarthexone (51) and the known fnarthexol (52) were isolated in the 1022 order of mg (18.0 and 24.0, respectively) from 8 kg of plant materials, thus providing a very 1023 low yield. On the contrary, conferol was isolated in huge amount (800 mg) accounting for 1024 0.01 % w/w. 1025 1026 7.14. The ferulosis 1027 In the context of bioactivities ascribed to Ferula spp., it is worth mentioning the case of 1028 “ferulosis”, a lethal haemorragic syndrome affecting sheeps, cattle, horses and goats (and 1029 even humans) (Carta, 1951a) caused by consumption of giant fennel (F. communis L.) (Carta, 1030 1951b; Carta and Delitala, 1951; Carta, 1955). This obviously leads to suffering of the 1031 affected animals that in many cases come to death, together with a negative impact on 1032 economy relying on animal resources. Several cases of ferulosis are reported in Sardinia 1033 (Appendino, 1997). The connection between the toxic symptoms and the consumption of 1034 giant fennel was demonstrated by the Sardinian veterinary Altara (Altara, 1925), who 1035 postulated the existence of two different chemotypes of giant fennel to explain the contrasting 1036 evidences of toxicity. The existence of two different chemotypes, undistinguishable by 41 1037 morphology, has been unambiguously confirmed by several phytochemical studies (Valle et 1038 al., 1986; Appendino et al., 1988a; Appendino et al., 1988b). Furthermore, several analytical 1039 approaches have been conducted to discriminate the two chemotypes on the basis of the 1040 presence (or absence) of specific chemical markers (Sacchetti et al., 2003; Rubiolo et al., 1041 2006; Alzweiri et al., 2015). Plants of the toxic chemotype showed the presence of prenylated 1042 4-hydroxy-coumarins with haemorragic properties such as ferulenol, 15-hydroxy-ferulenol, 1043 ferprenin. Conversely, these coumarins were not detected from the non-poisonous 1044 chemotype, which instead contained daucane sesquiterpenoids, some of which endowed with 1045 estrogenic properties, i.e. ferutinin (Valle et al., 1986; Appendino et al., 1988a; Appendino et 1046 al., 1988b; Appendino et al., 2001). It is interesting to note that within the toxic chemotype, 1047 highly poisonous plants were also recognized, which contain the polyacetylene falcarindiol 1048 endowed with pronounced antiplatelet activity (Appendino et al., 1993) besides the 1049 prenylated coumarins. In these higly poisonous plants, the contemporaneous presence of both 1050 polyacetylene and prenylated coumarins is most likely responsible of a synergistic toxicity. 1051 Fortunately, the toxic components have been identified and several analytical methods 1052 developed to discriminate between the two chemotypes. This is one clear case which 1053 demonstrates the importance of phytochemical analysis in both natural product studies and 1054 bioactivity and the primary role they have in the analysis of plant raw materials employed in 1055 botanicals, food supplements and phytotherapy (Toniolo et al., 2014). 1056 As just reported, a wide number of the newly described metabolites from Ferula spp. have 1057 been tested for their biological activities. Besides the quite common antioxidant 1058 characteristics, some of these compounds have showed a wide range of activities such as 1059 antimicrobial, antiviral (HIV), antibacterial (against multidrug-resistant and methicillin- 1060 resistant S. aureus) and antiprotozoal (against Leishmania and Plasmodium), thus offering 1061 new potentially useful compounds for the therapeutic treatment of various diseases. This is of 42 1062 potential importance considering that traditional antibiotics are losing their efficacy due to the 1063 emergence of new resistant disease-causing strains. On the other hand, new active molecules 1064 are becoming available for the treatment of diseases that have not been yet considered as 1065 drugs of choice. Furthermore, there are many drugs with reduced therapeutic indices and 1066 therefore high intrinsic toxicity. 1067 The antiprolifertive potential against several human cancer cell lines and the 1068 immunosuppresive activity, exerted by inhibition of the production of several cytokines, have 1069 been observed for several unusual metabolites from Ferula. In addition, there is the 1070 remarkable anti-inflammatory activity displayed by inhibition of both inflammation 1071 mediators and the mRNA expression of inflammatory factors such as iNOS, TNF-α, IL-6, IL- 1072 1β and COX-2. In this context, it is worth mentioning the antineuroinflammatory potential 1073 observed in microglial LPS-activated cells, since inflammatory and oxidative processes are 1074 considered as important factors in the etiopathogenesis of neurodegenerative diseases such as 1075 Alzheimer and Parkinson diseases and Multiple Sclerosis. Previous studies suggested that the 1076 ability to quench the induction of microglial activation might have interesting applications in 1077 several neurodegenerative and neuroinflammatory pathologies (Salemme et al., 2016) since it 1078 is known that microglia-dependent inflammation is strictly associated with the onset of 1079 neurodegenerative 1080 neuroinflammation. Therefore, the Ferula metabolites, which act as inhibitors of microglial 1081 activation, possess interesting potentialities also as possible neuroprotective agents. 1082 It should be also underlined that the majority of these compounds, in particular the newly 1083 described ones, are contained in their natural sources in very little amounts. Therefore, a 1084 possible estractive procedure to obtain them as pure compounds could be quite expensive 1085 considering the low yields that would be obtained. It is obviously not possible to exclude a 1086 priori that in the original works of their first description no exhaustive extraction has been diseases, characterized 43 by increased oxidative stress and 1087 obtained and that further studies in this sense can improve the yields. Anyway, in many cases, 1088 the extraction of the pure compounds seems to be the only possibility to use them because, 1089 given their small presence in the plant material, it is unlikely that they can give a biological 1090 effect when using the plant materials or the crude extract since the effective doses would not 1091 be achieved (Gertsch, 2009). This is an even more probable eventuality for those compounds 1092 which showed high values of IC50 i.e. ≥ 25 μM (Cos et al., 2006). A second limiting 1093 condition is that the majority of the described compounds have been tested only in in vitro 1094 assays. Nothing is known about their fate when administered to a living organism. The 1095 pharmacokinetic profile is an important factor to establish if a compound will be absorbed in 1096 sufficient amount to reach the effective dose and target tissues/organs, if it is metabolized and 1097 inactivated as well as if the eventual metabolites are still active or not. This in our opinion 1098 could be the future development regarding the bioactivity potential of the numerous 1099 metabolites isolated from Ferula species: the study of their pharmacokinetics and in vivo tests 1100 in order to obtain a complete picture of their real therapeutic and toxicological aspects. 1101 8. Propagation of Ferula species 1102 In recent years, the possibility to reproduce plants of Ferula spp. has also been studied by 1103 means of biothechnologic methods. To the date, there are only a few papers dealing with 1104 these aspects. Anyway, we are of the advice that in the future this area of research will be 1105 developed due to the high interest in the active secondary metabolites and the wide uses of 1106 Ferula spp. in the traditional medicine of several countries worldwide together with the 1107 increased interest in the protection of endangered species. Single node explants from F. 1108 orientalis L. were studied by Tuncer (2017) and shoots induction was obtained by culturing 1109 in Murashige/Skoog (MS) medium with the addition of 2,4-dichlorophenoxyacetic acid (2,4- 1110 D) and 6-benzylaminopurine (BAP) (0.5 and 2.0 mg/L, respectively) as plant growth 44 1111 regulators. With this method, the production of three shoots was obtained for each explants, 1112 thus resulting to be a useful in vitro regeneration method. Explants of root, hypocotyl and 1113 cotyledon (embryonal leaves) of F. assa-foetida L. were studied to evaluate the effects of 1114 different variables such as explants type, medium and plant growth regulators (Roozbeh et 1115 al., 2012). The results obtained in this study showed that the best somatic embryogenesis or 1116 the highest percent of induction was obtained from explants of leaves treated with 2,4-D (0.2 1117 mg/L) and KT (kinetin) (0.2 mg/L) in MS medium, while no significant effect was observed 1118 for both explants from cotyledon and hypocotyls. The best indirect somatic embryogenesis 1119 was instead obtained from roots explants treated with 2,4-D (0.5 mg/L) and KT (0.2 mg/L) in 1120 B5 medium. The maximum percentage of seedling development from embryos was found 1121 with simultaneous use of 2,4-D (0.5 mg/L) and KT (0.2 mg/L) as plant growth regulators in 1122 B5 medium, while the highest callogenesis induction was observed in B5 medium added with 1123 naphthaleneacetic acid (NAA) (1 mg/L) and KT (1 mg/L). A similar study was conducted by 1124 Zhu and colleagues (2009) in F. sinkiangensis K. M. Shen to explore the effect of different 1125 culture conditions and hormone combinations on callus induction. In addition, in this study 1126 different explants types were employed involving young cotyledon, hypocotyl and radicles. It 1127 resulted that the optimum medium for hypocotyl induction was MS added with 2,4-D (1.0 1128 mg/L) and KT (1.5 mg/L), while for radicle induction was MS added of NAA (0.5 mg/L) and 1129 BAP (0.5 mg/L) as plant growth regulators. The best subculture medium was MS added with 1130 NAA (1.5 mg/L) and BAP (2.5 mg/L), as well. The results were similar to those reported in 1131 the previous study with F. assa-foetida L. explants. It was observed that NAA, 2,4-D and 1132 BAP resulted to exert the inductive effect, while BAP showed better results than the KT in 1133 the proliferation step, and the GA3 (giberellin A3) had a coinductive role in the process of 1134 subculture embryogenic callus production. Somatic embryos production was also studied in 1135 F. gummosa Boiss. (Bernard et al., 2007) by induction of callus in zygotic embryonic axes in 45 1136 MS medium. The differentiation of tissues was obtained under induction with NAA and after 1137 the exposure to thermo-phototperiod of 16 h of light at 19 °C and 8 h in the dark at 7 °C. The 1138 maturation of embryos and development of plantlets were obtained in MS induction medium 1139 added with NAA or 2,4-D as plant growth regulators. However, better results were obtained 1140 after transfer in hormone free medium, even if a high percentage of abnormal embryos was 1141 recorded. A second study on F. gummosa Boiss. callus and organogenesis induction was 1142 conducted by Sarabadani et al. (2008). Moreover, various organs including roots, cotyledons, 1143 main leaf, hypocotyle, embryo and cutting embryo were used in the induction phase 1144 promoted by various combinations of plant growth regulators. In this relation, cutting 1145 embryos and roots were detected as best explants for callus induction with 1.2 mg/L-1 BAP 1146 and 10 mg/L-1 NAA as plant growth promoter, while shoot organogenesis was observed only 1147 under treatment with 1.5 mg/L-1 BAP and 0.5 mg/L-1 ADS (adenine sulfate) conditions. 1148 A new cryopreservation technique, based on vitrification of internal solutes, has been 1149 developed with the scope of conservation of seeds and embryonic axes obtained from F. 1150 gummosa Boiss. (Rajaee et al., 2012). The plant seeds were cultured to obtain the embryonic 1151 axes which were pre-treated in sucrose cultures prior to cryotreatment with liquid nitrogen by 1152 applying two different encapsulation-dehydration and vitrification methods. The major 1153 survival percentage of cryopreserved materials was obtained when the technique was applied 1154 on embryos. During this study, a higher percentage of germination was also recorded for 1155 embryonic axes in comparison with Ferula seeds subjected to natural germination. 1156 Dormancy break and germination induction were already studied earlier by Nadjafi and 1157 coworkers (2006) on the seeds of the same plant species (F. gummosa Boiss.) which were 1158 subjected to different treatments such as exposure to GA3, acid scarification with H2SO4 or 1159 HNO3, chilling and soaking in water at different temperatures. Accordingly, germination 46 1160 grade was noted after treatment with GA3 and dormancy breaking was efficiently obtained 1161 by chilling at 5 °C for two weeks. 1162 Other two studies which could give interesting information for what concerns the cultivation 1163 and conservation procedures were more recently conducted on F. jaeschkeana Vatke, a 1164 severely threatened medicinal plant native of the Himalayan region by Yaqoob and Nawchoo 1165 (2017b, a). Seed dormancy was interrupted after contemporaneous treatment with kinetin and 1166 dry stratification for 60 days and the higher percentage of germination was obtained after 24 1167 h of treatment with kinetin in sand:soil media (2:1). Differently, higher sprouting and rooting 1168 response in roots cuttings were observed after treatment with GA3 (500 ppm). Furthermore, 1169 the habitat variability impact on the reproductive success was studied. Several morphologic 1170 parameters (such as number of shoots per plant, root tuber dimensions, plant height, basal 1171 leaf length, pinnae number, pinnae length, pinnule length, number of flowering stems per 1172 plant, flowering stem length, sheath number per plant, sheath length, number of umbels, 1173 umbel diameter, umbels per flowering stem, umbellule’s per umbel, number of flowers, fruit 1174 morphology and fruit number) were considered to evaluate the reproductive success of this 1175 plant species. The best environmental conditions were also determined for a possible 1176 cultivation of this species as well as to develop effective strategies in the conservation of the 1177 wild populations and possibly for their sustainable use. In this study, it was concluded that 1178 the better conditions of growth of this species are those of altitudes comprised between 1500 1179 and 2000 m a.s.l.. 1180 9. Conclusion and future perspectives 1181 The increasing trend of industrialization and emergence of unknown and persistent diseases 1182 are among the greatest challenges to scientists in near future. Plant derivatives have exhibited 1183 novel therapeutic characteristics as a result of a large number of scientific investigations over 47 1184 the past few decades. Therefore, replacing chemical and synthesized drugs with natural-based 1185 plant products seems highly rational. The genus Ferula is the third largest genus of the 1186 Apiaceae family and comprises about 180 species mainly distributed in Asia, India and 1187 Mediterranean basin. Many of these species are endemic or indigenous entities with a 1188 consolidated use in the traditional medicines of the countries of origin. To date, a large 1189 number of bioactive compounds possessing interesting biological and medicinal activities 1190 have been separated from a wide array of Ferula plants. The present overview describes the 1191 large number of new compounds, which have been identified as components of Ferula 1192 species in recent decades, and makes note of the main ethnobotanical aspects of these species 1193 together with the pharmacological potentialities. The huge number of structures reported, 1194 belonging to different classes of natural products, highlighted the great variability in 1195 secondary metabolites in Ferula spp.. Several of them are metabolites restricted to this genus 1196 and, as such, are useful makers in the chemotaxonomy field. A great number of these new 1197 compounds resulted to be active as antibiotics against drug-resistant bacterial strains offering 1198 so new possible therapeutic approaches and new chemical structures, in comparison with 1199 those of traditional drugs, to develop new semisynthetic derivatives. Several Ferula 1200 metabolites resulted active against different tumor cell lines and, in the majority of the cases, 1201 showing little or no toxicity toward somatic cells. Both these two therapeutic areas, the 1202 microorganisms infections treatment and the chemotherapy of cancer, need new active 1203 molecules since the effectiveness of traditional drugs is decreasing due to the establishment 1204 of resistance and Ferula metabolites have demonstered to posses the potentiality to be 1205 effective drug candidates and to be useful starting materials to develop new semisynthetic 1206 derivatives. The inhibitory action in microglia-mediated neuroinflammation showed by some 1207 of the Ferula components is also worth of mention since this pathologic mechanism is widely 1208 considered responsible of the development of several neurodegenerative diseases. In this 48 1209 specific pharmaceutical field, only a little number of compounds resulted effective and the 1210 search of new active molecules is still in the limelight. Finally yet importantly, is noteworthy 1211 the antiprotozoal activity exerted by some metabolites against Leishmania and Plasmodium. 1212 There are currently very few drugs available for antiprotozoal therapy and the majority have a 1213 reduced therapeutic index due to their intrinsic toxicity. Differently from bacteria the 1214 protozoa offer limited and non-selective molecular targets, and this is one of the reasons why 1215 only a few compounds are currently available as antiprotozoal drugs. Therefore, the 1216 potentialities of Ferula metabolites represent a resource to be exploited in projecting new 1217 antiprotozoal molecules. Moreover, since only a limited number of species have been 1218 analyzed until now, we are of the opinion that several new components, also endowed with 1219 currently unexplored bioactivities, might be discovered in other so far unanalyzed species of 1220 the genus. We are also of the advice that the high pharmaceutical potential of Ferula 1221 metabolites will not go unnoticed by the scientific community and that in the future different 1222 studies will bring new developments, especially in the practical application of the various 1223 biological activities found so far. In conclusion, the presence in Ferula species of unusual 1224 bioactive phytochemicals demonstrates that this genus is a precious source of active natural 1225 products and has great potential in the pharmaceutical and medicinal fields. What is lacking 1226 in the current state of the art, for what concerns the bioactivity tests, is an approach that 1227 effectively assesses the therapeutic potential of these secondary metabolites through studies 1228 conducted in in vivo systems, and above all, investigating the pharmacokinetic aspects of 1229 compounds already resulted active in in vitro experiments. 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Molecules 19, 16959-16975. 2115 2116 87 2117 2118 2119 Table 1 Some endemic and indigenous species of the genus Ferula growing wild in different parts of the world. Country flora Italy Number 3 Iran 15 Turkey 9 Tunisia 4 Algeria 2 Pakistan 15 Saudi Arabia 4 India 3 Endemic/indigenous species Name Ferula arrigonii Bocchieri, F. communis L. and F. glauca L. F. pseudalliacea Rech.f., F. gabrielii Rech.f., F. kashanica Rech.f., F. persica Wild., F. macrocolea (Boiss.) Boiss., F. microcolea (Boiss.) Boiss., F. stenocarpa Boiss. & Hausskn, F. tabasensis Rech.f., F. behboudiana Rech. f. & Esfand, F. lutensis Rech.f., F. assa-foetida L., F. sharifii Rech.f., F. serpentinica Rech.f., F. flabelliloba Rech. f. & Aell. and F. xylorhachis Rech.f. F. amanicola Hub.-Mor. Et Pesmen, F. anatolica (Boiss.) Boiss., F. drudeana Korovin, F. halophila Pesmen, F. huber-morathii Pesmen, F. longipedunculata Pesmen, F. lycia Boiss., F. parva Freyn et Bornm. and F. tenuissima Hub.-Mor. et Pesmen F. communis L., F. tingitana L., F. tunetana Pomel ex Batt. and F. lutea (Poir.) Maire F. logipes Coss. ex Bonnier and Maury (also named F. cossoniana Batt.) and F. vesceritensis coss. et Dur. F. assa-foetida L., F. baluchistanica, F. communis L., F. costata, F. hindukushensis, F. jaeschkeanaVatke, F. kokanica Rgl. et Schmalh., F. lehmannii Boiss., F. microloba Boiss., F. narthex (Falc.) Drude, F.oopoda (Boiss. Et Buhse) Boiss., F. ovina Boiss., F. reppiae, F. rubicaulis, and F. stewartiana F. communis var. communis L./var. glauca (L.) Rouy and Camus, F. ovina (Boiss.) Boiss., F. rutbaensis C.C. Townsend. and F. sinaica Boiss. F. narthex (Falc.) Drude, F. thomsoni and F. jaeschkeana Vatke 2120 2121 2122 88 Ref. (Conti et al., 2005; Maggi et al., 2009b) (Mozaffarian, 1996) (Pesmen, 1972; Saǧiroǧlu and Duman, 2010) (Jabrane et al., 2010; Znati et al., 2012) (Labed-Zouad et al., 2015) (Anonymous; Yaqoob and Nawchoo, 2016) (Anonymous; Yaqoob and Nawchoo, 2016) (Hooker, 1897) Table 2 Remedial traditional, pharmaceutical and medicinal properties of the different species from the genus Ferula growing wild in different parts of the world. Ferula species Organ/part Properties Different parts Tonic, spice and as a strong antioxidant, antibacterial, antifungal, anticoagulant, antimicrobial, anti-ulcer, anticonvulsant, antispasmodic, antiinflammatory, antihelmintic, antidiabetic, aphrodisiac, alterative, hypotensive, sedative, laxative, stimulant, diuretic, neuroprotective and carminative remedy; widely administered to address asthma, impotence, bronchitis, flatulence, infection, stomachache, hysteresis; as a flavoring agent to table sauces and for seasoning the food products, to lower blood pressure, acting as a vermifuge when its decoction is taken orally Promising neuroprotective impact against the cultured neurons, a proper remedy for intestinal parasites, whooping cough, emmenagogue, influenza, gasterointestinal problems, insects and snake bites, respiratory malfunctions, an antifertility, antihepatotoxic, antihyperglycemic and antiviral drug, an acaricide, anticholesterol and anticarcinogenic plant F. assa-foetida L. OGR 1 Aerial parts, flowers, leaves, seeds, stems and roots F. gummosa Boiss. 2 Used as/for; prescription mode Decoction, extract, row, air dried, and fried Country/continent Ref. Iran, Asia (Mahran et al., 1973; Zargari, 1990; Rafiq Siddiqui et al., 1995; Sefidkon et al., 1998; Dehpour et al., 2009; Iranshahy and Iranshahi, 2011; Mahendra and Bisht, 2012; Amiri, 2014) Raw Iran, Asia As a flavoring agent and condiment in the vegetarian diet of the Indian people and in Indian pickles Effective against amenorrhea when is being chewed Effective in the treatment of stomach problems, flatulence, chronic, antibacterial, bronchitis, colic, chorea as well as some neurological disorders, tonic, as an anti-hysteric, antihemolytic, anti-diarrhea, antiparasitic, antinociceptive, antioxidant, emmenagogue, antispasmodic, anti-inflammatory, anti-convulsant, decongestant, analgesic, digestive, expectorant, uterine tonic drug, stimulant, epilepsy, and as an effective wound healing remedy, to withdraw morphine Raw India, Asia (Heravi, 1967; Mahran et al., 1973; Samsam Shariat and Moattar, 1990; SamsamShariat, 1992; Keshri et al., 1999; Mallikarjuna et al., 2003; Iranshahy and Iranshahi, 2011; Kanani et al., 2011; Moghadam et al., 2013; Ghannadi et al., 2014; Hadavand Mirzaei and Hasanloo, 2014; Homayouni Moghadam et al., 2014; Fatemikia et al., 2017) (Guenther, 1952) Raw Air dried, raw, poultice, and extract Malaysia, Asia Iran, Asia Used as a carminative and softening agent, a proper remedy against seizure, earache, asthma, headache, chorea, epilepsy and stomachache, inflammation, in wound healing, and to address liver disorders and inability; industrial uses: to prepare varnishes and paints of high Raw Japan, Iran, Asia 89 (Buddrus et al., 1985) (Zargari, 1990; Fazly-Bazzaz et al., 1997; Ramezani et al., 2001; Eftekhar et al., 2004; Mandegary et al., 2004; Iranshahi et al., 2010a; Nabavi et al., 2010; Kanani et al., 2011; Mozaffarian, 2012; Amiri, 2014; Mahboubi, 2016) (Howlett, 1980; Panda, 2003; Javidnia et al., 2005; Mortazaienezhad and Sadeghian, 2006; OGR Aerial parts Roots F. communis L. 3 Rhizomes Roasted flower Fresh kernel F. foetida Regel F. microcolea (Boiss.) Boiss. Aerial parts Roots Aerial parts, flowers, leaves, and stems Different parts qualities, as a flavoring agent or emulsifier to food products and beverages and additive to some detergents and soaps To address some disorders and diseases like rheumatism, bronchitis, acne, poor circulation, muscle, aches, stretch marks and to improve scars, wounds, sores and cuts; serving as a proper aphrodisiac, antihysteric, anti-diabetic, anti-nociceptive, antiseptic, anti-catarrh, and as an analgesic drug Raw, extract Iran, Asia Mohammadzadeh Milani et al., 2007; Miyazawa et al., 2009; Mahboubi, 2016) (Sayyah et al., 2001; Mandegary et al., 2004; Kouyakhi et al., 2008; Fallah et al., 2015) As a medicinal plant from antiquity for the treatment of dysentery, an antihysteric agent Acting as a strong female sterilizing agent, an analgesic, anti-helmintic, and diuretic remedy as well as in the treatment of rheumatism, joins pains and in hair care To treat skin disorders Effective against dysentery and hay fever Treating of snakebite, hysteria, convulsion, diarrhea, diabetes, dizziness and stomachache, to improve muscle cramps, to stop bleeding Edible with high diuretic, antispasmodic and anthelminthic potentials Effective to cure of backache and rheumatism As a spice, food additive and flavoring agent and acting as an antioxidant agent Raw and dried Different parts of the world Morocco, Africa (Heywood, 1971; Mohammadhosseini, 2016) (Nguir et al., 2016) Saudi Arabia, Asia Some African countries Iran, Asia (Collenette, 1985) Iran, Asia (Zargari, 1990; Amiri, 2014) Lebanon and Syria, Asia United States of America India, Asia (Lev and Amar, 2002; Hadidi et al., 2003) (Hadidi et al., 2003) (Sadraei et al., 2001; Radulović et al., 2013) (Sadraei et al., 2001; Radulović et al., 2013) (Afifi and Abu-Irmaileh, 2000; Amiri, 2014) (Zhang and Hu, 1987; Yang et al., 2006; Xiaojin and Jiang Lin, 2007; Yang et al., 2007; Zhang et al., 2015; Li et al., 2016; Xing et al., 2017) (Yang et al., 2006) As a tonic aphrodisiac agent 4 Raw Raw and dried Dried and crushed Raw and dried Raw, dried, crushed, extracts Raw and dried F. hermonis Boiss. Aerial parts F. jaeschkeana Vatke F. galbaniflua Boiss. & Buhse F. rubricaulis Boiss. F. persica Wild. Resin F. sinkiangensis K. M. Shen Aerial parts F. teterrima Kar. & Kir. Aerial parts Recommended as a highly aphrodisiac in the American dietary supplement protocols Antiseptic agent Raw and dried An additive to candy and to address intestinal malfunctions Aerial parts and stems Aerial parts and stems Raw, dried or powder form Raw and dried Iran, Asia Raw and dried Xinjiang, China, Asia Galbanum An additive to candy and to address intestinal malfunctions Aerial parts, roots To treat lumbago, backache, rheumatism and diabetes; as a potent carminative, laxative, and antihysteric agent Having immunopharmacological, anti-inflammatory, antibacterial, antiulcerative activities as well as remedial properties against stomach problems along with rheumatoid arthritis; an antioxidant, anti-tumor and a deodorant agent; in the preparation of a special Chinese food; acting as neuroinflammation inhibitors5 For the treatment of rheumatoid arthritis along with intestinal (stomach) problems 90 Raw Iran, Asia Iran and Jordan, Asia Xinjiang, China, Asia (Boulos, 1983; Dioscorides, 2000) (Zargari, 1990) (Anonymous, 1948) Aerial parts An anti-cholinergic, anti-spasmodic remedy with remarkable smooth muscle relaxant properties, as a condiment and spice Air dried, raw, and extract Jordan, Asia Aerial parts and roots Aerial parts In vitro apoptosis and cytotoxic influences 6; antimicrobial impacts Raw and dried Iran, Asia Lowering blood pressure and enhancing intestinal muscle contractibility in rabbits and to cure inflammation Kazakhstan, Asia Aerial parts To cure peptic disease Juice, extracts and essential oils Raw and dried China, Asia (Tan et al., 2017) Different parts Resins To treat infant colic An antihysteric agent; used as an effective remedy against insects, dysentery, feminine sterility, hay fever, colon, asthma, spasm, epilepsy, rheumatism and malaria Raw and dried Raw and dried Iran, Asia China, Asia; African countries Aerial parts In the treatment of bronchitis along with rheumatoid arthritis Raw and dried Aerial parts Roots Raw and dried Dried powder Aerial parts To flavor the local pickles Ruminant feeding (sheep and cattle); promotion of the rate of animal fertility As a sedative drug, effective against abdominal pain and diarrhea Central Asia (arid lands) Turkey, Europe Turkey, Europe Raw and dried Iran, Asia (Iranshahi et al., 2008) (Boulos, 1983; Trease and Evans, 1983; Martinetz and Lohs, 1988; Habibi et al., 2006b) (Motai and Kitanaka, 2005b; Xing et al., 2017) (Kartal et al., 2007) (Miski et al., 1983; Klevenhusen et al., 2015) (Lahazi et al., 2015) Aerial parts As a sedative drug, effective against abdominal pain and diarrhea Raw and dried Iran, Asia (Lahazi et al., 2015) Aerial parts Raw and dried Iran, Asia (Saghravanian et al., 2016) Aerial parts, flowers and stems To relief pain due to its impact on different receptors involving adenosine, cannabinoid and cannabinoid Known as a strengthening agent and also an appetite stimulator; an antimicrobial agent Raw and dried Turkey, Europe (Özek et al., 2008) Roots Recommended against epilepsy and spasms Raw and dried Iran, Asia (Asili et al., 2009) Aerial parts As a strong anti-hysteric, decongestant and anticonvulsant remedy, effective in treating some neurological disorders and a tonic herbal drug Raw and dried Tunisia, Africa (Eigner and Scholz, 1990; Afifi and Abu-Irmaileh, 2000; Znati et al., 2017) Different parts Extract, raw and dried Extract Iran, Asia (Esmaeili et al., 2009) Underground parts Representing remarkable antiplasmodial and remedial features against migraine as well as cough Spasmolytic activity Serbia, Europe (Pavlović et al., 2014) Aerial parts, leaves, flowers and For the treatment of persistent headache, throat infections and fever, having antioxidant and antibacterial properties Fresh and dried Algeria, Africa (Benchabane et al., 2012; Labed-Zouad et al., 2015) F. ovina (Boiss.) Boiss. F. iliensis Krasn. ex Korov F. syreitschikowii Koso-Pol. F. latisecta Rech. f. & Aell F. fukanensis K.M.Shen F. orientalis L. F. elaeochytris Korovin F. flabelliloba Rech. F. et Aell F. diversivittata Regel & Schmalh. F. szowitsiana DC. 7 F. badrakema Koso-Pol. F. badrakema Koso-Pol. and F. gummosa Boiss. (Mixed together) F. oopoda (Boiss. & Buhse) Boiss. F. heuffelii Griseb. ex Heuffel F. vesceritensis Coss. & Dur 8 91 (Al-Khalil et al., 1990; Aqel et al., 1992; Radulović et al., 2013) (Amooaghaie, 2009; Matin et al., 2014) (Aqel et al., 1992; Özek et al., 2017) F. tingitana L F. cupularis (Boiss.) Spalik et S. R. Downie stems Different parts Flowers, leaves and stems As an abortive plant with high menstruation-inducing properties; recommended for the treatment of indigestion, fever, pains and sore throat To cure ulcer and also to preserve foodstuffs (oil and meat) Libya, Africa (Elghwaji et al., 2017) Dried parts Iran, Asia (Alipour et al., 2015) As one of the potential sources of asafoetida representing traditional and Raw and dried Iran, Asia (Kasaian et al., 2016) medical uses like F. assa-foetida L. 1 Oleo-gum-resin; 2 Known as "Barijeh" and "Ghasni" in the Iranian folk medicine; 3 Giant fennel formerly known as "Narthex" by the Romans; 4 Known as "Lebanese Viagra";5 Due to the presence of sesquiterpene coumarins; 6 Related to ferutinin isolated from the roots of F. ovina (Boiss.) Boiss.; 7 Known as “Sivas Kasnisi” in Turkish traditional folk medicine; 8 Traditionally known as "Kelkha" F. alliacea Boiss. Different parts Fresh and dried 92 Table 3 Main components of essential oils, oleo-gum-resins, volatile constituents and extracts from different species of Ferula genus growing wild in different parts of the world. Plant name (s) F. L. assa-foetida F. elaeochytris Korovin F. flabelliloba Rech. F. et Aell F. stenocarpa Boiss. & Hausskn F. gummosa Boiss. Major constituents (%) Limonene (26.0%), pcymene (14.3%), α-pinene (8.3%), and terpinen-4-01 (5.8%) Nonane (27.1%), α-pinene (12.7%), and germacrene B (10.3%) δ-Cadinene (13.2%), αcadinol (12.0%), and cadina-4,1(10.0)-dien-8β-ol (10.9%), and α-pinene (10.0%) α-Pinene (48.8%) and βpinene (30.1%) EO f: Limonene (14.0%), αpinene (13.0%), myrcene (10.0%), terpinolene (10.0%), linalool (9.0%), δ3-carene (9.0%), γterpinene (6.0%), phellandral (5.0%), butyl isovalerate (3.0%), α-terpinolene (2.5%), β-pinene (2.0%), and hexyl isovalerate (2.0%) EE g: β-Pinene (62.0%), αpinene (34.0%), and δ-3carene (4.0%) PE h: Guaiole (31.0%), βpinene (21.0%), valencene (14.0%), α-pinene (11.0%), YEO a Prevailing group Extraction method (s)/Solvent Analysis or characterization methods (s) Organ(s)/Part(s) Country 1.0 MH b HD c GC and GC-MS Oleo-gum-resin 0.27 NH d HD GC-MS 0.87 OS e HD 0.33 MH HD 18 MH HD Identified Ref. Number % India 44 97.9 (Garg et al., 1989) Fruits Turkey 43 76.7 (Baser et al., 2000) GC and GC-MS Aerial parts Iran 20 80 (Rustaiyan et al., 2001b) GC and GC-MS Aerial parts Iran 26 97.8 (Rustaiyan et al., 2001a) >30 88 GC-FID and GCMS Oleo-gum resin (Sadraei et al., 2001) Iran 26 MH Ether 3 100 25 MH Petroleum ether 6 99 93 F. gummosa Boiss. F. ovina (Boiss.) Boiss. F. galbaniflua Boiss. et Buhse. F. microcolea (Boiss.) Boiss. F. hirtella Boiss. F. communis L. F. persica Wild. F. L. assa-foetida δ-cadinene (11.0%), and pyrimidine (10.0%) ME i: Benzene-1-3dimethyl (38.0%), benzene1-2-dimethyl (16.0%), benzene ethyl (12.0%), and benzene-1ethyl-2-methyl (4.0%) β-Pinene (50.1%), α-pinene (18.3%), δ-3-carene (6.7%), α-thujene (3.3%), and sabinene (3.1%) Carvacrol (9.0%), α-pinene (8.2%), geranyl isovalerate (7.2%), and geranyl propionate (7.0%) β-Pinene (46.4%), cischrysanthenyl acetate (6.1%), (E)-nerolidol (5.2%), and α-pinene (2.8%) β-Pinene (58.8%), cischrysanthenyl acetate (6.1%), and (E)-nerolidol (5.2%) α-Pinene (19.2%), nonane (13.2%), and β-pinene (13.0%) α-Pinene (15.4%), and thymol (14.9%) Myrcene (53.5%), and aristolene (8.5%) Dill-apiole (57.3%), and elemicine (5.6%) (E)-1-Propenyl sec-butyl disulfide (40.0%), and germacrene B (7.8%) (E)-1-Propenyl sec-butyl disulfide (50.3-59.4%) l 15 NH MeOH 6-7 MH HD GC and GC-MS Fruits 1.0 OM j HD GC-MS Aerial parts 1.2 4 70 Iran 17 94.6 (Sayyah et al., 2001) Iran 43 86.7 (Ghannadi et al., 2002) 41 87.4 Stem MH HD GC and GC-MS 3.0 Root 1.5 MH HD GC and GC-MS (Rustaiyan and Monfared, 2002) Iran Aerial parts 34 86.1 30 88.9 35 84.8 Iran 0.4 HD GC, GC-MS and 13C-NMR Leaves Corsica 47 95.0 0.2 HD GC and GC-MS Aerial parts Iran 61 93.7 1.13 HD 25 94 NR k MH NH 0.8-5.5 SFE m: Supercritica l fluid extraction GC and GC-MS NR Iran 16-22 94 91.899 (Akhgar et al., 2005) (Ferrari et al., 2005) (Javidnia et al., 2005) (Khajeh et al., 2005) F. macrocolea (Boiss.) Boiss. F. ferulaoides Korov. F. gummosa Boiss. F. szowitsiana DC. n F. latisecta Rech. f. & Aell F. persica Willd. var. persica F. szovitsiana D.C. β-Pinene (15.9%), α-pinene (10.4%), and βcaryophyllene (8.6%) Guaiol (58.8%), (E)nerolidol (10.2%), and αeudesmol (3.0%) β-Pinene (43.8%), α-pinene (27.3%), and myrcene (3.4%) α-Pinene (12.6%), germacrene D (12.5%), βpinene (10.1%), epi-αcadinol (8.9%), myrcene (7.0%), bicyclogermacrene (5.6%), and β-phellandrene (5.6%) (Z)-Ocimenone (32.4%), (E)-ocimenone (20.3%), and cis-pinocarvone (11.4%) Dimethyl trisulphide (18.2%), myristicin (8.9%), dimethyl tetrasulphide (7.6%), α-terpinyl npentanoate (5.8%), lavandulyl 2-methyl butanoate (3.7%), α-terpinyl isovalerate (3.5%), and αbarbatene (3.1%) Neryl acetate (33.0%), βcaryophyllene (8.9%), αpinene (8.0%), β-pinene (6.7%), bicyclogermacrene (4.5%), caryophyllene oxide (4.1%), limonene (4.6%), and α-terpineol (3.2%) Neryl acetate (41.5%), bicyclogermacrene (9.0%), α-pinene (5.5%), β-pinene (3.9%), γ-cadinene (3.5%), and calarene (3.2%) NR MH HD GC-MS Aerial parts Iran 42 86.3 (Rustaiyan et al., 2005) 2.4-3.2 OS HD GC-MS Air-dried roots Mongolia 42 95.8 (Shatar, 2005) 4.0 MH HD GC-MS Air-dried fruits Iran 73 96.9 (Ghasemi et al., 2005) 0.3 SH o HD GC and GC-MS Aerial parts Iran 23 100 (Habibi et al., 2006a) 0.4 OS HD GC and GC-MS Aerial parts Iran 22 87.7 (Habibi et al., 2006b) 0.15 NH HD GC and GC-MS Root Iran 39 82.0 (Iranshahi et al., 2006) 51 97.7 0.18 Stem/Leaves OM HD GC and GC-MS 0.2 Flower/fruits 95 (Dehghan et al., 2007) Iran 47 95.9 F. latisecta Rech. F. et Aell. sec-Butyl-(Z)-propenyl disulphide (65.2%), secbutyl-(E)-propenyl disulphide (6.8%), and disec-butyl disulphide (2.1%) 2.0 NH HD GC and GC-MS Fruits Iran 41 88.9 (Iranshahi et al., 2008) F. gummosa Boiss. β-Pinene (26.8-69.2%), and α-pinene (1.4-33.9%) 1.663.85 MH HD GC and GC-MS Fruits Iran 9-21 79.4100 (Kouyakhi et al., 2008) 4.0 MH HD GC, GC-MS and 13C-NMR Fruits Iran 74 98.2 (Asili et al., 2009) 0.94 NH HD GC-MS Aerial parts Iran 61 98.8 (Dehpour et al., 2009) Leaves 60 87.3 Flowers 82 96.8 Fruits 19 68.7 SH Roots 23 79.7 0.05 SH Leaves 74 89.8 0.06 SH 95 92.8 0.09 MH 55 79.1 F. badrakema Koso-Pol. F. L. assa-foetida F. glauca L. p β-Pinene (45.8%), α-pinene (10.9%), cisisolongifolanone (4.1%), βphellandrene (2.7%), myrcene (2.4%), and carvacrol methyl ether (2.4%) Phenol, 2-methyl-5-(1methyl ethyl) (18.2%), αbisabolol (10.4%), and arsine triethyl (8.7%) (E)-Caryophyllene (24.9%), and caryophyllene oxide (14.3%) Germacrene D (14.2%), myrcene (13.6%), and αpinene (11.7%) α-Pinene (24.2%), and βpinene (14.7%) SH 0.020.07 (E)-β-Farnesene (10.0%), elemicin (9.0%), and myristicin (7.4%) F. glauca L. (E)-Caryophyllene (20.5%), caryophyllene oxide (13.9%), and germacrene D (6.8%) Germacrene D (16.4%), myrcene (10.1%), (E)caryophyllene (9.4%), and α-pinene (6.8%) α-Pinene (36.6%), β-pinene (17.8%), and myrcene (4.1%) SH HD MH HD GC-FID and GCMS GC-FID and GCMS Italy Flowers Fruits 96 Italy (Maggi et al., 2009a) (Maggi et al., 2009b) F. L. assa-foetida F. lycia Boiss F. Rech. Aell. latisecta f. and F. oopoda (Boiss. & Buhse) Boiss. F. badghysi Elemicin (9.0%), (E)-βfarnesene (8.4%), αzingiberene (6.9%), myristicin (6.0%), and βbarbatene (4.0%) Sample 1 q: (E)-1-Propenyl sec-butyl disulfide (30.7%), 10-epi-γ-eudesmol (12.7%), (Z)-1-propenyl sec-butyl disulfide (12.4%), methyl l(methylthio) propyl disulfide (10.9%), eudesmol (7-epi-α) (4.8%), and agarospirol (2.8%) Sample 2 r: (E)-1-Propenyl sec-butyl disulfide (18.8%), 10-epi-γ-eudesmol (18.7%), (Z)-1-propenyl sec-butyl disulfide (9.2%), 7-epi-αeudesmol (8.2%), agarospirol (5.1%), and methyl l-(methylthio) propyl disulfide (4.3%) α-Pinene (59.9%), β-pinene (19.0%), limonene (3.2%), and bornyl acetate (2.1%) sec-Butyl-(Z)-propenyl disulfide (50.5%), sesquicineol-2-one (7.2 %), sec-butyl-(E)-propenyl disulfide (6.2%), and δcadinene (2.9%) β-Phellandrene (22.4%), thymol-methyl ether (15.3%), and myrcene (8.7%) Myrcene (36.1%), βphellandrene (28.2%), and germacrene D (5.5%) β-Phellandrene (21.7%), thymol-methyl ether 0.03 SH Roots 0.8 NH HD GC and GC-MS Roots 54 76.3 26 98.5 (Mirzaei and Hasanloo, 2009) Iran 1.6 26 93.3 NR MH HD GC-MS Roots Turkey 36 96.8 (Kose et al., 2010) 0.3 NH HD GC-MS Roots Iran 14 73.3 (Sahebkar et al., 2010) 16 97.3 20 98.2 17 95.8 0.9 1.1 Leaves MH HD GC and GC-MS 0.7 Seeds Leaves 97 Iran (Akhgar et al., 2011) (Korovin.) F. hermonis Boiss. F. ovina (Boiss.) Boiss. F. foetida (Bunge) Regel F. L. assa-foetida (13.8%) and myrcene (13.5%), α-ylangene (11.3%) Myrcene (32.8%), βphellandrene (24.1%), and germacrene D (6.8%) α-Pinene (43.3%), αbisabolol (11.1%), and 3,5nonadiyne (4.4%) Fresh: Limonene (16.9%), α-pinene (15.2%), βmyrcene (7.7%), cis-βocimene (6.1%), isosylvestrene (5.1%), and β-pinene (4.4%) Dried: α-Pinene (20.2%), spathulenol (9.6%), germacrene D (6.3%), βcaryophyllene (5.1%), α-terpineol (5.0%), and caryophyllene oxide (4.4%) 2,3,4-Trimethylthiophene (49.0%), 2,5diethylthiophene (27.5%), elemicine (8.1%), and αpinene (3.4%) 1-Methylpropyl (1E)-prop1-en-1-yl disulfide (32.8%), α-pinene (11.3%), 1methylpropyl (1Z)-prop-1en-1-yl disulfide (9.1%), and β-pinene (6.1%) 1.2 1.5 Seeds MH HD GC-FID, GC-MS and 13C-NMR Rhizome and roots Jordan 0.4 MH HD GC and GC-MS Aerial parts 22 94.7 79 92.8 42 95.0 (Azarnivand et al., 2011) Iran 0.25 21 91.1 NH 14 97.3 NH 18 81.3 NR HD GC-FID and GCMS Aerial parts (Kanani et al., 2011) Iran F. behboudiana (Rech. f. & Esfand.) Chamberlain Sabinene (75.3%), (E)caryophyllene (16.1%), and α-pinene (2.0%) MH 13 99.1 F. flabelliloba Rech. f. & Aell. epi-α-Cadinol (17.8%), (E)-γ-bisabolene (8.0%), and α-pinene (5.4%) SH 33 84.2 F. hirtella Boiss. Germacrene B (15.5%), SH 16 87.0 98 (Al-Ja'Fari et al., 2011) F. latisecta Rech. f. & Aell. bicyclogermacrene (12.9%), α-pinene (9.9%), γ-elemene (8.5%), germacrene-D (8.5%), β-elemene (6.3%), β-pinene (4.6%), and limonene (4.4%) α-Pinene (51.6%), β-pinene (13.7%), limonene (10.0%), and sabinene (5.5%) α-Pinene (33.5%), spathulenol (8.2%), citronellyl acetate (5.3%), and β-elemene (5.1%) α-Pinene (55.0%), camphene (20.5%), limonene (4.8%), limonene (4.8%), and sabinene (4.1%) MH 23 96.9 MH 24 96.6 MH 17 98.7 1-Methylpropyl (1Z)- prop1-en-1-yl disulfide (88.1%), and 1-methylpropyl (1E)prop-1-en-1-yl disulfide (5.0%) NH 8 98.8 F. diversivittata Regel & Schmalh. Verbenone (69.4%), and arcurcumene (6.2%) OM 22 87.3 F. galbaniflua Boiss. & Buhse β-Pinene (59.0%), and αpinene (36.6%) MH 12 99.9 F. gummosa Boiss. β-Pinene (66.3%), α-pinene (20.3%), and δ-3-carene (8.6%) β-Pinene (40.7%), βphellandrene (22.7%), αpinene (16.2%), and δcadinene (7.2%) α-Pinene (37.3%), and βpinene (36.2%) MH 10 98.8 MH 16 93.2 MH 18 97.3 F. persica Willd. var. latisecta F. persica Willd. var. persica F. szowitsiana DC. F. stenocarpa Boiss. & Hausskn. F. hezarlalehzarica 99 Y. Ajani F. macrocolea (Boiss.) Boiss. F. microcolea (Boiss.) Boiss. F. orientalis Boiss. F. ovina (Boiss.) Boiss. F. ovina (Boiss.) Boiss. F. ovina (Boiss.) Boiss. F. ovina (Boiss.) Boiss. (Z)-β-Ocimene (41.7%), and myrcene (35.3%) α-Pinene (21.9%), β-pinene (17.8%), (Z)-caryophyllene (6.2%), caryophyllene oxide (4.6%), (E)-caryophyllene (4.4%), and limonene (4.3%) α-Pinene (41.2%), nonane (16.0%), β-pinene (13.8%), myrcene (4.7%), limonene (4.4%), and sabinene (4.3%) Nonane (45.6%), α-pinene (32.1%), and 2- methyl octane (19.4%) α-Pinene (61.0%), myrcene (6.3%), limonene (6.3%), and camphene (5.6%) α-Pinene (63.8%), camphene (6.5%), and limonene (4.9%) α-Pinene (68.7%), myrcene (4.7%), camphene (4.2%), β-pinene (4.2%), and limonene (4.1%) MH 11 85.3 MH 18 89.3 MH 16 99.4 NH 12 99.4 MH 16 91.5 MH 11 83.7 MH 12 90.1 F. ovina (Boiss.) Boiss. α-Pinene (65.4%), and βpinene (5.1%) MH 18 92.1 F. oopoda (Boiss. & Buhse) Boiss. α-Terpinyl acetate (73.3%), sabinene (19.7%), and αpinene (1.1%) MH 10 99.0 F. sinkiangensis K. M. Shen n-Propyl sec-butyl disulfide (55.8%) 3.8 26 99.1 F. fukangensis K. M. Shen n-Propyl sec-butyl disulfide (49.8%) 1.2 21 100 NH HD GC-MS 100 Seeds China (Li et al., 2011) F. ovina (Boiss.) Boiss. n-Propyl sec-butyl disulfide (53.8%) F. vesceritensis coss. et Dur. Viridiflorol (13.4%), δcadinene (10.1%), and farnesol (8.1%) A mixture of 1-sec-butyl-2[(E)-3-(methilthio) prop-1-enyl] disulphane and 1-sec-butyl-2-[(Z)-3(methilthio) prop-1-enyl] disulphane (59.4%), glubolol (12.5%), α-pinene (8.8%), α-bisabolol (6.1%), and β-pinene (3.9%) 2,3,6-Trimethyl benzene (25.0%), cis-chrysanthenol (20.8%), α-pinene (10.9%), and thymol (10.2%) (E)-1-Propenyl-sec-butyl disulfide (62.7%), βocimene (21.7%), and βpinene (5.0%) F. behboudiana (Rech. f. & Esfand.) Chamberlain F. lutea Poiret F. L. F. L. assa-foetida assa-foetida Sample 1 s: (E)-1-Propenyl sec-butyl disulfide (25.5%), (Z)-1propenyl sec-butyl disulfide (23.0%), bis [(1-methylthio) propyl] disulfide (11.0%), bulnesol (4.3%), agaruspirol (4.0%), germacerene B (3.2%), hinesol (2.5%), and guaiol acetate (2.3%) Sample 2 t: (Z)-1-propenyl sec-butyl disulfide (23.9 %), bis [(1methylthio) propyl] disulfide (19.4%), (E)-1propenyl sec-butyl disulfide 1.8 0.1 OS 25 99.5 HD GC and GC-MS Leaves Algeria 89 96.8 (Benchabane et al., 2012) Aerial parts Iran 27 97.2 (Yousefi et al., 2011) 0.9 NH HD GC, GC-MS, 1HNMR, 13C-NMR, DEPT, H-HCOSY, C-HCOSY and HMBC 1.0 OM HD GC and GC-MS Aerial parts Algeria 21 84.9 (Chibani et al., 2012) 7.0 NH HD GC-MS Latex Iran 11 99.9 (Kavoosi et al., 2012) 41 93.5 2.3 NH HD GC and GC-MS 2.85 Seeds (Mirzaei and Hasanloo, 2012) Iran 42 101 97.3 (18.8%), bulnesol (6.7%), and αbisabolol (3.1%) F. heuffelii Griseb. ex Heuffel F. L. assa-foetida F. L. assa-foetida F. L. assa-foetida Elemicin (35.4%), and myristicin (20.6%) epi-α-Cadinol (23.2%), germacrene B (11.0%), αgurjunene (6.2%), (Z)-1propenyl sec-butyl disulfide (5.9%), 5-epi-7-epi-αeudesmol (4.9%), δcadinene (4.8%), γ-cadinene (3.4%), and germacrene D (3.1%) (E)-1-Propenyl-sec-butyl disulfide (62.7%), βocimene (21.7%), and βpinene (5.0%) OGR v1: (E)-1-Propenyl sec-butyl disulfide (23.9%), 10-epi-γ-eudesmol (15.1%), (Z)-1-propenyl sec butyl disulfide (8.0%), (Z)-βocimene (5.6%), αeudesmol (4.5%), α-pinene (4.4%), β-pinene (4.2%), βdihydroagarofuran (4.1%), γ-eudesmol (3.5%), guaiol (3.0%), agarospiral (3.0%), limonene (2.9%), αphellandrene (2.9%), (E)-βocimene (2.5%), 5-epi-7epi-αeudesmol (2.1%), and βeudesmol (1.1%) OGR2: (Z)-1-Propenyl secbutyl disulfide (27.7%), 0.08 NH 0.3 SH NR NH 9.0 NH 6.0 GC and GC-MS Underground parts Serbia 67 94.4 (Pavlović et al., 2012) GC-MS Fruit Iran 54 96.9 (Bahramia et al., 2013) HD GC-MS Leaves and latex Iran NR NR (Kavoosi and Purfard, 2013) 45 99.7 HD GC and GC-MS OGR Iran 45 99.9 HD SDSE u NH 102 (Kavoosi and Rowshan, 2013) F. L. assa-foetida F. microcolea (Boiss.) Boiss F. L. assa-foetida F. vesceritensis Coss. & Dur F. ovina (Boiss.) (E)-1-propenyl sec-butyl disulfide (20.3%), α-pinene (10.7%), β-pinene (10.2%), (Z)-β-ocimene (7.8%), 10-epi-γ-eudesmol (5.3%), (E)-β-ocimene (2.9%), and β-dihydroagarofuran (1.8%) OGR3: β-Pinene (47.1%), and α-pinene (21.3%), 1, 2dithiolane (18.6%), nitrite propyl (3.6%), thionol (2.6%), (Z)-β-ocimene (2.4%), and (E)-β-ocimene (1.4%) β-Pinene (47.1%), α-pinene (21.4%), and 1,2-dithiolane (18.6%), nitrite propyl (3.7%), thionol (2.6%), and cis-β-ocimene (2.4%) α-Pinene (27.3%), β-pinene (16.4%), nonanal (8.7%), βcaryophyllene (8.5%), and thymol (6.7%) (E)-1-Propenyl sec butyl disulphide (56.0%), 1-(1propenylthio) propyl methyl disulfide (16.9%), and 1,2dithiolane (5.7%) x (E)-1-Propenyl sec-butyl disulfide (28.8%), (Z)-1propenyl sec-butyl disulfide (14.4%), and 1-(1propenythio) propyl methyl disulfide (10.1%) y β-Pinene (24.3%), α-pinene (17.3%), limonene (10.0%), β-myrcene (6.6%), and carotol (6.1%) α-Pinene (25.7%), myristcin 4.0 MH NR MH HD GC and GC-MS Latex 1.1 MH HD GC and GC-MS ADHP w 45 100 Iran 15 98.5 (Kavoosi et al., 2013) Iran 22 93.6 (Amiri, 2014) 14 NR 10.6 NH HD GC-MS Resins (Divya et al., 2014) India 1.9 16 NR 1.4 MH HD GC-FID and GCMS Seeds Algeria 50 96 (Bouratoua et al., 2014) 0.28 MH HD GC and GC-MS Aerial parts Iran 14 100 (Mohammadhosse 103 Boiss. F. orientalis L. F. cupularis (Boiss.) Spalik et S. R. Downie (10.1%), limonene (9.6%), camphene (9.5%), δ-3carene (9.3%), linalool (7.4%), and citronellol (5.6%) Myristcin (14.7%), limonene (12.2%), α-pinene (9.6%), myrcene (9.5%), endo-fenchyl acetate (5.7%), and camphene (4.3%) α-Pinene (23.9%), limonene (17.0%), myrcene (16.0%), camphene (8.3%), myristcin (4.9%), and bornyl acetate (4.0%) Myrcene (26.0%), α-pinene (17.6%), limonene (18.4%), camphene (4.3%), and endo-fenchyl acetate (3.0%) α-Cadinol (10.4%), δcadinene (8.1%), germacrene D-4-ol (6.8%), epi-α-muurolol (5.9%), and α-pinene (5.7%) α-Cadinol (11.7%), germacrene D-4-ol (11.9%), δ-cadinene (9.3%), α-pinene (7.2%), and epi-α-muurolol (6.1%) Limonene (25.0%), δ-2carene (15.8%), sabinene (8.0%), βphellandrene (6.9%), αterpinolene (5.6%), δ-3carene (5.2%), p-mentha-1en-9-ol (2.8%), and γterpinene (2.2%) β-Pinene (13.9%), βocimene (9.0%), ini and Nekoei, 2014) 0.24 SFME z 30 95.6 0.33 MWHD aa 20 97.4 28 98.2 69 83.4 HS-SPME - ab Leaves NR OS HD GC and GC-MS Flowers 0.36 MH Flowers HD 0.45 GC and GC-MS MH 68 84.3 30 98.6 36 93.7 Iran Leaves 104 (Ozkan et al., 2014) Turkey (Alipour et al., 2015) F. vesceritensis Coss. & Dur. bornyl angelate (6.6%), allo-ocimene (6.1%), trans-isolimonene (5.8%), dihydro-linalool acetate (5.0%), β-phellandrene (4.2%), pmentha-1,5,8-triene (4.0%), α-terpinyl isobutyrate (3.7%), terpin-4-ol (3.4%), cis-dihydro- α-terpinyl acetate (3.1%), δ-2-carene (2.9%), camphene (2.7%), neo-allo-ocimene (2.7%), citronellyl nbutyrate (2.6%), decane (2.4%), and α-phellandrene (2.4%) α-Terpinyl isobutyrate (8.7%), δ-3-carene (8.4%), bornyl angelate (7.4%), transsabinol (6.9%), sothol (6.0%), p-cymen-9-ol (5.5%), terpinyl acetate (5.2%), linalool isobutyrate (3.4%), camphor (3.0%), βbourbonene (2.7%), p-menth-1-en-9-ol acetate (2.6%), citronellyl butyrate (2.6%), myrcenone (2.4%), trans-sabinyl acetate (2.2%), and iso-verbanol acetate (2.2%) α-Pinene (32%), carotol (13.9%), fenchyl acetate (10.4%), α-phellandrene (8.5%), and aristolene (5.4%) α-Phellandrene (24.3%), α- 0.39 OM 1.8 MH 1.6 MH Stem HD GC-FID and GCMS FF ac DF ad 105 Algeria 32 91.9 42 97.9 37 88.6 (Labed-Zouad et al., 2015) pinene (16.1%), carotol (10.7%), and elixene (6.3%) Carotol (18.8%), α-pinene (11.5%), β-pinene (8.1%), caryophyllene oxide (7.6%), fenchyl acetate (7.3%), aristolene (7.2%), and elixene (5.4%) α-Pinene (17.4%), carotol (10.8%), β-pinene (8.9%), fenchyl acetate (8.8%), and aristolene (6.8%) S1: (E)-Propenyl sec-butyl disulfide (40.4%), (Z)propenyl sec-butyl disulfide (23.1%), β-pinene (9.7%), (E)-β-ocimene (5.5%), and α-pinene (4.7%) ag S2: (E)-Propenyl sec-butyl disulfide (40.3%), (Z)propenyl sec-butyl disulfide (22.1%), β-pinene (10.7%), α-pinene (5.0%), n-propyl sec-butyl disulfide (4.1%), and (E)-β-ocimene (3.2%) 1.6 OS FS ae 48 96.4 1.4 MH DS af 36 87.4 7.79 18 97.4 10.07 24 97.7 ah S3: (E)-Propenyl sec-butyl disulfide (44.4%), (Z)propenyl sec-butyl disulfide (22.8%), β-pinene (9.6%), (E)-β-ocimene (6.3%), and α-pinene (4.2%) ai S4: (E)-Propenyl sec-butyl disulfide (50.0%), β-pinene (14.9%), (Z)-propenyl secbutyl disulfide (13.5%), αpinene (5.1%), n-propyl sec-butyl disulfide (3.6%), and (E)-β-ocimene (2.6%) aj S5: (E)-Propenyl sec-butyl disulfide (49.1%), (Z)- NH HD GC and GC-MS Resin (Moghaddam and Farhadi, 2015) Iran 8.52 16 97.2 7.39 22 98.9 8.36 19 97.3 106 propenyl sec-butyl disulfide (12.1%), β-pinene (12.0%), α-pinene (6.2%), n-propyl sec-butyl disulfide (3.7%), and (E)-β-ocimene (2.5%) ak S6: (E)-Propenyl sec-butyl disulfide (37.3%), (Z)propenyl sec-butyl disulfide (17.8%), β-pinene (11.8%), α-pinene (6.7%), (E)-βocimene (4.0%), and npropyl sec-butyl disulfide (2.5%) al S7: (E)-Propenyl sec-butyl disulfide (42.6%), (Z)propenyl sec-butyl disulfide (17.2%), β-pinene (14.4%), α-pinene (5.1%), n-propyl sec-butyl disulfide (5.0%), and (E)-β-ocimene (2.6%) 7.24 27 96.3 8.10 16 98.1 8.53 30 99.0 9.52 26 97.3 42 96.5 am S8: (E)-Propenyl sec-butyl disulfide (52.2%), (Z)propenyl sec-butyl disulfide (13.2%), β-pinene (9.5%), α-pinene (4.2%), n-propyl sec-butyl disulfide (4.0%), and (E)-β-ocimene (2.9%) an S9: (E)-Propenyl sec-butyl disulfide (54.0%) and (Z)propenyl sec-butyl disulfide (12.7%), β-pinene (8.0%), α-pinene (5.6%), n-propyl sec-butyl disulfide (4.0%), and (E)-β-ocimene (3.0%) ao F. gummosa Boiss. γ-Elemene (14.1%), germacrene B (11.8%), (E)γ-bisabolene (10.7%), viridiflorene (8.1%), and 0.32 SH HD GC and GC-MS 107 Aerial parts Iran (Mohammadhosse ini et al., 2015) epizonaren (6.2%) F. lutea (Poir.) Maire F. Boiss. alliacea F. communis L. F. communis L. Aromadendrene (17.6%), germacrene B (16.2%), γelemene (6.5%), (E)-γbisabolene (6.3%), and βelemene (5.1%) δ-3-Carene (72.6%), αpinene (5.8%), myrcene (5.1%), and α-phellandrene (4.0%) 10-epi-γ-Eudesmol (22.3%), valerianol (12.5%), hinesol (8.3%), guaiol (7.3%), and Zpropenyl-sec-butyl trisulphide (6.5%) α-Pinene (10.5%), hedycariol (8.4%), and γterpinene (7.6%) α-Pinene (55.9%), β-pinene (16.8%), and myrcene (5.9%) β-Eudesmol (12.1%), αeudesmol (12.1%), and hedycariol (10.3%) (E)-β-Farnesene (9.5%), βcubebene (8.2%), and (E)caryophyllene (7.2%) Camphor (18.3%), α-pinene (15.3%), β-eudesmol (9.3%), caryophyllene oxide (8.0%), and myrcene (5.0%) β-Eudesmol (28.1%), δeudesmol (11.1%), and αeudesmol (9.6%) Dillapiole (7.9%), guaiol (7.3%), spathulenol (6.8%), myristicin (6.0%), and Tcadinol (5.9%) 0.4 SH SFME 0.09 MH HD GC(FID), GC-MS and 13C-NMR Roots 0.13 OS HD GC-MS Roots 0.13 MH 0.03 MH HD 39 98.4 Tunisia 9 95.1 (Ben Salem et al., 2016) Iran 76 99.5 (Kasaian et al., 2016) Flowers 80 95.1 Fruits 102 97.7 GC-FID and GCMS (Maggi et al., 2016) Italy 0.06 OS Leaves 73 95.5 0.02 SH Roots 50 70.9 0.18 OS Flowers 32 97.3 0.15 OS 39 91.3 0.024 OS 20 90.4 HD GC and GC-MS Stems Roots 108 Tunisia (Nguir et al., 2016) F. communis L. F. akitschkensis B.Fedtsch. ex Koso-Pol. F. clematidifolia Koso-Pol. F. gummosa α-Eudesmol (25.2%), βeudesmol (20.7%), δeudesmol (10.1%), and caryophyllene oxide (7.2%) Bizerte: Chamazulene (9.3%), α-humulene (6.4%), α-cubebene (6.4%) and caryophyllene (4.0%) Rades: α-Terpinene (7.4%) and germacrene B (7.1%) Gammarth: α-Eudesmol (12.3%), caryophyllene oxide (5.5%), α-pinene (5.0%), ar-curcumene (5.0%), γ-cadinene (5.0%) and γ-terpinene (5.0%) Soliman: Sabinene (58.7%), α-pinene (15.4%), β-pinene (8.5%), terpinen-4-ol (3.9%), eremophilene (1.4%), 2-himachalen-7-ol (1.3%), and trans-sabinene hydrate (1.0%) Myristicin (67.9%), and elemicine (0.8%) Myrcene (34.3%), limonene (30.1%), sabinene (16.5%), β-phellandrene (7.0%), αpinene (2.5%), and β-pinene (1.6%) β-Pinene (36.9%), α-pinene (29.3%), sabinene (8.1%),bicyclogermacrene (5.5%), myrcene (3.9%), germacrene D (3.2%), and (3E,5Z)-1,3,5-undecatriene (2.0%) β-Pinene (50.1%), α- pinene (14.9%), δ-3-Carene 0.11 OS 0.022 SH 0.38 SH Leaves HD GC-MS Leaves 28 94.7 53 88.9 54 78.70 Tunisia 0.22 OS 59 75.5 0.11 OS 97 98.7 0.7 MH 52 98 Stems 21 96.6 Leaves 29 100 Umbels + seeds HD 0.02 GC and GC-MS NH 0.1 MH HD GLC-MS 0.4 NR Kazakhstan MH HD GC-MS 109 Resins Iran (Schepetkin et al., 2016) (Sharopov et al., 2016) Tajikistan Roots (Rahali et al., 2016) 33 99.4 17 98 (Fatemikia et al., 2017) Boiss. F. gummosa Boiss. F. tingitana L. F. iliensis Krasn. ex Korov F. tunetana Pomel ex Batt. (6.7%), α-thujene (3.3%), sabinene (3.1%), and alloocimene (2.9%) β-Pinene (31.8%), α-pinene (11.4%), β-eudesmol (8.9%), and caryophyllenol (7.4%) β-Pinene (23.9%), α-pinene (13.0%), β-eudesmol (8.4%), and α-bisabolol (6.7%) β-Pinene (36.3%), α-pinene (16.3%), limonene (3.7%), and α-bisabolol (3.6%) β-Pinene (20.2%), α-pinene (8.9%), bornyl acetate (9.9%), and fenchyl acetate (8.4%) β-Pinene (38.6%), α-pinene (13.0%), β-eudesmol (7.5%), and fenchyl acetate (6.9%) α-Thujene (13.5%), elemol (8.9%), and cadinol (2.2%) Cadinol (13.8%), eudesmol (9.7%), elemol (8.3%), and α-thujene (2.3%), (E)-Propenyl sec-butyl disulfide (15.7-39.4%) and (Z)-propenyl sec-butyl disulfide (23.4-45.0%) ap α-Pinene (39.8%), β-pinene (11.5%), and (Z)-β-ocimene (7.5%) 0.22 Roots 31 97.9 0.36 Stems 35 94.2 33 90.9 1.2 MH HD GC-MS Flowers Iran 0.1 Leaves 34 90.2 14.7 Galbanum 32 98.4 Flowers 28 0.06 OS HD GC-MS (Elghwaji et al., 2017) Libya Leaves (Najafabadi et al., 2017) 0.1 OS NR NH aq HD GC-MS Dried plant material Kazakhstan 25-46 8491.7 (Özek et al., 2017) 0.12 MH HD GC, GC-MS and 13C-NMR Seeds Tunisia 18 84.6 (Znati et al., 2017) a 32 YEO: Yield of essential oil; b MH: Monoterpene hydrocarbon; c HD: Hydrodistillation; d NH: Non-terpene hydrocarbon; e OS: Oxygenated sesquiterpene; f EO: Essential oil; EE: Etheric extract; h PE: Petrolic extract; i ME: Methanol extract; j OM: Oxygenated monoterpene; k NR: Not reported; l Over run 1-9; m SFE: Supercritical fluid extraction; n Syn. F. khorasanica Rech. F. et Aell. and F. microloba Boiss.; o SH: Sesquiterpene hydrocarbon; p Formerly considered as a subspecies of F. communis; q From Gonabad, Iran; r From Tabas, Iran; s From Razavi Khorsan Province, Iran (Tabas); t From Kohsorkhe-Kasmar, Iran; u SDSE: Steam distillation solvent extraction method; v OGR: Oleogum-resin; w ADHP: Air-dried herbal parts; x From Pathani, India; y From Irani, India; z SFME: Solvent free microwave extraction; aa MWHD: Microwave hydrodistillation; ab HS-SPME: Headspace-solid phase microextraction; ac FF: Fresh flowers; ad DF: Dry flowers; ae FS: Fresh stems; af DS: Dry stems; ag S1: From Koohpaye, Iran; ah S2: From g 110 Jangale Ghaem, Iran; ai S3: From Joopar, Iran; aj S4: From Khomroot, Iran; ak S5: From Pabdana, Iran; al S6: From Rayen, Iran; am S7: From Sardoo, Iran; an S8: From Sirjan, Iran; ao S9: From Shahr Babak, Iran; ap From flowers, leaves, stems, roots in the flowering period as well as seeds and umbels (fruits) together with roots in the fruiting period; aq Mainly composed of sulfur-containing compounds 111 Fig. 1. The photographs taken from F. assa-foetida L., A: in the marginal parts of Semnan province, Iran; B: separated leaves and flowers; C: fresh aerial parts. 112 Fig. 2. A: Photograph of F. assa-foetida L. taken by E. Karimi (PhD candidate in agriculture) in the full flowering stage, B and C: local foods prepared by dried stems and aerial parts of F. assa-foetida L. 113 Fig. 3 Sulfur-containing, aliphatic, cyclic and aromatic compounds identified in the essential oils of 18 Ferula species: (Z)-1-(sec-butyl)-2-(prop-1-en-1-yl)disulfane (1), 2,3,4-trimethylthiophene (2), (E)-1-(sec-butyl)-2-(prop-1-en-1-yl)disulfane (3), 2-methyloctane (4), (1R,5R)-4,6,6trimethylbicyclo[3.1.1]hept-3-en-2-one (5), 2,5-diethylthiophene (6), 1,3-dimethyltrisulfane (7), 4,7,7-trimethylbicyclo[4.1.0]hept-4-en-3-ol (8), 1,2-di((E)-but-2-en-2-yl)disulfane (9), 2-ethyl3,6-dimethoxybenzaldehyde (10), 3,7-dimethyloct-6-en-1-yl propionate (11) and (E)-hex-1-en-1yl(phenethyl)sulfane (12) (Kanani et al., 2011). 114 Fig. 4. Eight bioactive hemiterpene coumarin derivatives, fesumtuorin A-H (13-20), separated from F. sumbul (Kauffm.) Hook.f. (Zhou et al., 2000). 115 Fig. 5. The molecular structures of the isolated ferulagol A (21) and ferulagol B (22) in the extract of F. assa-foetida L. (roots) (El-Razek et al., 2001). 116 Fig. 6. The characterized sesquiterpenoids pallidones A-F (23-28) and isolated in the ethyl acetate extract obtained from F. pallida Korovin roots (Su et al., 2000). 117 Fig. 7. The molecular structures of the isolated assafoetidnol A (29) and assafoetidnol B (30) in the extract of F. assa-foetida L. (roots) (Abd El-Razek et al., 2001). 118 Fig. 8. The main bioactive compounds (31-36) separated from F. fukanensis K.M.Shen (Motai et al., 2004). 119 Fig. 9. The molecular structures of the four sesquiterpene coumarins (37-40) obtained from the 80% aqueous methanol extract of the roots of F. fukanensis K.M.Shen (Motai and Kitanaka, 2004). 120 Fig. 10. The molecular structure of saradaferin (41) separated from the EtOAc extract of F. assa-foetida L. (OGR) (Bandyopadhyay et al., 2006). 121 Fig. 11. The sesquiterpenoid coumarins (42-44) isolated from the ethanol extract obtained from F. teterrima Kar. & Kir. and F. sinkiangensis K. M. Shen roots (Yang et al., 2006). 122 Fig. 12. The main sesquiterpene derivatives (45-47) characterized in the methanol extract from the roots of F. gummosa Boiss. (Iranshahi et al., 2010a). 123 Fig. 13. The molecular structures of three newly characterized sesquiterpenoid coumarins, ferulin A-C (48-50), extracted from the roots of F. ferulaeoides (Steud.) Korov (Meng et al., 2013a). 124 Fig. 14. The structures of sesquiterpene coumarins (51-52) from F. narthex Boiss (Bashir et al., 2014a). 125 Fig. 15. The structures of the three sesquiterpenoid coumarins (53-55) separated from the roots of F. ferulioides (Steud.) Korovin (Liu et al., 2015). 126 Fig. 16. The molecular structures of newly characterized disesquiterpene coumarins (56-57) separated from F. pseudalliacea Rech.f. (Dastan et al., 2012). 127 Fig. 17. The molecular structure of sinkiangenorin D (58) as a newly characterized sesquiterpene coumarin separated from the seeds of F. sinkiangensis K. M. Shen (Li et al., 2015a). 128 Fig. 18. The sesquiterpene coumarins (59-60) isolated from F. sinkiangensis K. M. Shen (Li et al., 2015b). 129 Fig. 19. The main bioactive compounds (61-62) separated from F. sinkiangensis K. M. Shen (Xing et al., 2017). 130 Fig. 20. The molecular structures of characterized coumarin esters derivatives (63-64) separated from F. orientalis L. (Razavi et al., 2016). 131 Fig. 21. The molecular structure of ferulone C (65), a ester coumarin, isolated from roots of F. persica Wild (Razavi and Janani, 2015). 132 Fig. 22. The molecular structures of the two dihydrofuranocoumarin esters obtained from the roots of F. lutea (Poir.) Maire, (−)-5-hydroxyprantschimgin (66) and (−)-5-hydroxydeltoin (67) (Ben Salem et al., 2013). 133 Fig. 23. The molecular structures of kuhistanols A-D (68-71) from F. kuhistanica Korovin (Chen et al., 2000a). 134 Fig. 24. The molecular structures of the farnesyl hydroxybenzoic acid derivatives (72-75) in the F. kuhistanica Korovin MeOH extract of roots (Chen et al., 2001). 135 Fig. 25. The main sesquiterpene chromone derivatives (76-80) separated from a watermethanol extract of F. fukanensis K.M.Shen (roots) (Motai and Kitanaka, 2005a). 136 Fig. 26. The molecular structures of the two sesquiterpene chromone derivatives, ferulin D,E (81-82) extracted from the roots of F. ferulaeoides (Steud.) Korov (Meng et al., 2013a). 137 Fig. 27. The molecular structures of five daucane-type sesquiterpenes (83-87) characterized in the methanolic extract of F. kuhistanica Korovin (stems and roots) (Chen et al., 2000b). 138 Fig. 28. The molecular structures of the eudesmanolide (88) and carotene (89) derivatives in the organic extract of F. sinaica Boiss. (Ahmed et al., 2001). 139 Fig. 29. The molecular structure of (1S,4S,5R,6S,7S,10S)-5,10,11-cadinanetriol (90) separated from an acetone extract of the air-dried ground roots of F. communis L (Appendino et al., 2001). 140 Fig. 30. The molecular structure of 2,3-α-epoxyjaeschkeanadiol-5-benzoate (91) separated from a methylene chloride extract of F. hermonis Boiss (roots) (Diab et al., 2001). 141 Fig. 31. The main daucane esters (92-93) separated from a hexane extract of F. hermonis Boiss (roots) (Galal et al., 2001). 142 Fig. 32. The main daucane esters (94-96) separated from an EtOAc extract of F. kuhistanica Korovin. (dried fruits) (Tamemoto et al., 2001). 143 Fig. 33. Seventeen bioactive sesquiterpene compounds (97-113) separated from F. penninervis Regel and Schmalh (Shikishima et al., 2002). 144 Fig. 34. The molecular structures of three daucane sesquiterpenes (1R,4R)-4-hydroxydauca7-ene-6-one (114), (1R,4R)-4-hydroxydauca-7-ene-6,9-dione (115), and (1R,3S,8S)-3-ethoxy8-angeloyloxydauca-4-en-9-one (116), separated from an hexane extract of F. hermonis Boiss (roots) (Lhuillier et al., 2005). 145 Fig. 35. The molecular structures of the six sesquiterpene lactones (117-122) obtained from from the roots of F. varia (Schrenk) Trautv. (Suzuki et al., 2007). 146 Fig. 36. The molecular structures of five characterized sesquiterpene derivatives (123-127) separated from the dichloromethane extract of F. vesceritensis Coss. & Dur, organ: aerial parts (Oughlissi-Dehak et al., 2008). 147 Fig. 37. The molecular structures of the two sesquiterpene esters obtained from the roots of F. elaeochytris Korovin, 6-anthraniloyljaeschkeanadiol (elaeochytrin A) (128) and 4βhydroxy-6α-(p-hydroxybenzoyloxy)dauc-9-ene (elaeochytrin B) (129) (Alkhatib et al., 2008). 148 Fig. 38. The molecular structures of the sesquiterpene, badrakemonin (130), obtained from the roots F. badrakema Koso-Pol (Iranshahi et al., 2009). 149 Fig. 39. The molecular structures of the four sesquiterpene lactones (131-134) obtained from from the roots of F. diversivittata Regel & Schmalh. (Iranshahi et al., 2010b). 150 Fig. 40. Molecular structures of a characterized ester (135) and a coumarin sesquiterpene derivative (136) from the roots of F. tunetana Pomel ex Batt (Jabrane et al., 2010). 151 Fig. 41. The molecular structures of three daucane sesquiterpenes (137-139) isolated from the roots of F. communis subsp. communis (Dall’Acqua et al, 2011). 152 Fig. 42. The molecular structures of three daucane esters (140-142 and 141a) separated from an n-hexane-ethyl acetate (1:1) extract of the ground seeds of F. hermonis Boiss (Auzi et al., 2008; Ibraheim et al., 2012a). 153 Fig. 43. The components, sesquiterpene lactone glycosides (143-149), separated from the water-soluble fraction obtained from the methanol extract of F. varia (Schrenk) Trautv. roots (Kurimoto et al., 2012b). 154 Fig. 44. bioactive compounds (150-157) separated from a water extract of F. varia (Schrenk) Trautv roots (Kurimoto et al., 2012a). 155 Fig. 45. The structures of the four sesquiterpene resacetophenones (158-161) separated from the roots of F. ferulioides (Steud.) Korovin (Liu et al., 2015). 156 Fig. 46. The molecular structures of the four polysulphanes (162-165) isolated from the aerial parts of F. behboudiana Rech. f. Esfand (Yousefi et al., 2010). 157 Fig. 47. The main bioactive sulfur-containing compounds (166-170) separated from a dichloromethane extract of F. latisecta Rech.f. & Aellen (Soltani et al., 2018). 158 Fig. 48. The molecular structures of the isolated sulfur-containing compounds foetithiophenes C-F (171-174) in the petroleum ether extract from the roots of F. foetida Regel (Chitsazian-Yazdi et al., 2015). 159 Fig. 49. The main bioactive compound, a caffeic acid cinnamyl ester, namely (2E)-3,4dimethoxycinnamyl-3-(3,4-diacetoxyphenyl) acrylate (175) separated from F. assa-foetida L. (Abd El-Razek, 2007). 160 Fig. 50. Eight bioactive sesquiterpenoids--ferulaeone A-H (176-183)—isolated from aqueous-ethanol (5:95, v/v) extracts of the roots of F. ferulaeoides (Steud.) Korov (Meng et al., 2013b). 161 Fig. 51. The molecular structure of the saponin (sandrosaponin XI) (184) isolated from the root of F. hermonis Boiss. (Ibraheim et al., 2012b). 162 Fig. 52. The molecular structures of steroidal esters sinkiangenorin (185), sinkiangenorin B (186) and sinkiangenorin C (187), isolated from the seeds of F. sinkiangensis K. M. Shen (Li et al., 2014). 163 Fig. 53. Two compounds (188, 189) separated from F. lutea (Poir.) Maire (Znati et al., 2014). 164