Reviews
A Review of the Phytochemistry, Traditional Uses, and Biological
Activities of the Genus Ballota and Otostegia1
Affiliations
1 Department of Agricultural, Food and Forest Sciences
(SAAF), University of Palermo, Viale delle Scienze,
Parco dʼOrleans II, IT-90128 Palermo, Italy
2 Department of Biological, Chemical and Pharmaceutical
Sciences and Technologies (STEBICEF), University of
Palermo, Viale delle Scienze, Parco dʼOrleans II, IT-90128
Palermo, Italy
Correspondence
Prof. Sergio Rosselli
Department of Agricultural, Food and Forest Sciences (SAAF),
University of Palermo
Viale delle Scienze, Parco dʼOrleans II – IT-90128 Palermo,
Italy
Phone: + 39 0 91 23 89 75 47
sergio.rosselli@unipa.it
Key words
Ballota, Otostegia, secondary metabolites, antioxidant,
antibacterial, antifungal
AB STR AC T
received
revised
accepted
January 24, 2019
June 5, 2019
June 7, 2019
Bibliography
DOI https://doi.org/10.1055/a-0953-6165
Published online | Planta Med © Georg Thieme Verlag KG
Stuttgart · New York | ISSN 0032‑0943
Introduction
The genus Ballota, belonging to Lamiaceae family (Stachyoideae/
Lamioideae subfamily) [1, 2], is, apart from the South African endemic species Ballota africana (L.) Benth., naturally distributed in
the Mediterranean, the Middle East and in North Africa. Some species (e.g., Ballota nigra L. s. l.) are also present over large areas of
western, central, and northern Europe, and 4 species, whose status will be discussed later, in Somalia.
Ballota species are perennial herbs or small shrubs with
branched and/or simple hairs, toothed and petiolate leaves, the
inflorescence thyrsoid or racemoid sometimes has long and spinose bracteoles (sect. Acanthoprasium), and the calyx is mostly
campanulate, purple to white.
A former classification of the genus identified the occurrence
of 31 species (1 = Ballota integrifolia Benth. – 2 = Ballota wettsteinii
Rech. pat. – 3 = Ballota frutescens (L.) Woods – 4 = Ballota fruticosa
Baker – 5 = Ballota somala Patzak – 6. Ballota andreuzziana Pamp. –
Rosselli S et al. A Review of …
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The 2 genera Ballota and Otostegia, belonging to the Lamiaceae family, are closely related taxonomically and found
mainly in the Mediterranean area, Middle East, and North Africa. Since ancient times, they have been largely employed in
traditional medicine for their biological properties such as
antimicrobial, anti-inflammatory, antispasmodic, insecticidal,
anti-malaria, etc. Phytochemical investigations of Ballota and
Otostegia species have revealed that diterpenoids are the
main constituents of the genera. A large number of flavonoids
and other metabolites were also identified. This review, covering literature from 1911 up to 2018, includes traditional uses,
chemical profiles (both of volatile and nonvolatile metabolites), and biological properties of all the taxa of these 2 genera studied to date.
7 = Ballota acetabulosa (L.) Benth. – 8 = Ballota undulata (Sieb, ex
Fres.) Benth. – 9 = Ballota pseudodictamnus (L.) Benth. – 10 = Ballota damascena Boiss. – 11 = Ballota hildebrandtii Vatke et Kurtz –
12 = Ballota hirsuta Benth. – 13 = Ballota bullata Pomel – 14 =
B. africana (L.) Benth. – 15 = Ballota aucheri Boiss. – 16 = Ballota
macrodonta Boiss. et Bal. – 17 = Ballota larendana Boiss. et Heldr.
– 18 = Ballota rotundifolia C. Koch – 19 = Ballota rupestris (Biv.) Vis.
– 20 = Ballota macedonica Vand. – 21 = Ballota kaiseri V. Täckh. –
22 = Ballota antilibanotica Post – 23 = Ballota cristata Davis – 24 =
Ballota semanica Rech. f. – 25 = Ballota labillardieri Briq. – 26 = Ballota saxatilis Sieb. ex J. et C. Presl – 27 = Ballota stachydiformis
Höchst. – 28 = Ballota philistea Bomm. – 29 = Ballota platyloma
1
Dedicated to Professor Dr. Cosimo Pizza in recognition of his important
contributions to natural product research on the occasion of his 70th
birthday in 2019.
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Authors
Sergio Rosselli 1, Gianfranco Fontana 2, Maurizio Bruno 2
A B B R E V I AT I O N S
ABTS
Ac
AD
ALP
AP
BuOH
CAT
CQ
CUPRAC
DPPH
EO
EtOAc
EtOH
F
FRAP
GSH
L
LPO
MBC
MeOH
MIC
MPO
MTT
n-Hex
NO
NOE
ORAC
PE
R
S
SGOT
SGPT
SOD
STZ
TB
TBARS
TEAC
TG
VLDL
W
WP
X/XO
2,2′-azino-bis(3-ethylbenzothiazoline-6sulphonic acid)
acetone
agar diffusion
alkaline phosphatase
aerial parts
butanol
catalase
chloroquine
cupric ion reducing antioxidant capacity
2,2-diphenyl-1-picrylhydrazyl
essential oil
ethyl acetate
ethanol
flowers
ferric reducing antioxidant power
gluthatione
leaves
linoleic acid peroxidation
minimum bactericidal concentration
methanol
minimum inhibiting concentration
myeloperoxidase
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
n-hexane
nitric oxide
nuclear Overhauser effect
oxygen radical absorbance capacity
petroleum ether
root
stems
serum glutamic oxaloacetic transaminase
serum glutamine-pyruvate transaminase
superoxide dismutase
streptozotocin
total bilirubin
thiobarbituric acid reactive substances
Trolox equivalent absorbance capacity
triglycerides
very low density lypoproteins
water
whole plant
hypoxanthine/xanthine redox couple
Rech. f. – 30 = B. nigra L. – 31 = Ballota royleoides Benth.) which
were divided into 10 sections [3–5].
In subsequent years, several modifications and additions were
made to the former classification.
The 4 Somalian species, B. fruticosa, B. somala, B. hildebrandtii,
and B. stachydiformis were moved to other genera and now their
accepted names are Otostegia modesta S. Moore, Isoleucas somala
(Patzak) Scheen (syn. Otostegia somala (Patzak) Sebald), Otostegia
hildebrandtii (Vatke & Kurtz) Sebald, and Leucas stachydiformis
(Benth.) Hochst. ex Briq., respectively [6]; B. integrifolia and
B. wettsteinii are both considered synonyms of Acanthoprasium integrifolium (Benth.) Ryding (accepted name) [7]; B. frutescens,
B. labillardieri, B. semanica, and B. rupestris are synonyms of Acanthoprasium frutescens (L.) Spenn. [7], B. saxatilis, B. saxatilis subsp.
brachyodonta (Boiss.) P. H. Davis & Doroszenko, and Ballota
hispanica (L.) Benth., respectively [6].
The Plant List [6], which has been used to validate the scientific
names of the species, includes more than 160 scientific plant
names of species rank for the genus Ballota. Of these, only 30 are
accepted species names.
The genus Otostegia (Lamiaceae family, Stachyoideae/Lamioideae subfamily), closely related to genus Ballota morphologically,
with about 15 species, occurs in rather dry, often montane areas
and semideserts [8]. There are 2 clearly disjoint centers of diversity for Otostegia: Central Asia to Afghanistan and northeastern
Africa [9], although the genus is distributed from Cameroon to
Saudi Arabia, Yemen, Egypt, Iran, and Central Asia to India [8].
In 2007, Scheen & Albert [10] proposed to restrict the Otostegia genus, including only the following 11 species in it: Otostegia
ellenbeckii Gürke, Otostegia ericoidea Ryding, Otostegia erlangeri
Gürke, Otostegia fedtschenkoana Kudr., Otostegia fruticosa (Forssk.)
Schweinf. ex Penzig, O. hildebrandtii, Otostegia migirtiana Sebald,
O. modesta, Otostegia olgae (Regel) Korsh., Otostegia sogdiana
Kudr., and Otostegia tomentosa A. Rich. The former members of
Otostegia, O. somala and Otostegia aucheri, were transferred to
Isoleucas and Moluccella, respectively. A new genus was erected
for the 4 yellow-flowered species of Otostegia (Otostegia integrifolia Benth., Otostegia limbata [Benth.] Boiss, Otostegia michauxii
Briq., Otostegia persica (Burm. f.) Boiss), for which the name Rydingia A.-C. Scheen & V. A. Albert was proposed. Consequently, the
4 names actually accepted for these species are Rydingia integrifolia (Benth.) Scheen & V. A. Albert, Rydingia limbata (Benth.)
Scheen & V. A. Albert, Rydingia michauxii (Briq.) Scheen & V. A.
Albert, Rydingia persica (Burm. f.) Scheen & V. A. Albert [6].
The Plant List [6] is generally in agreement with this classification of genus Otostegia. It reports 46 name records of species rank
for the genus Otostegia, of which only 10 species and 3 subspecies
are accepted. In addition to the above-mentioned species [10], the
Plant List added Otostegia nikitinae Scharasch. and Otostegia schennikovii Scharasch., while moving Otostegia bucharica B. Fedtsch.,
O. fedtschenkoana, O. olgae, and O. sogdiana to genus Moluccella [7].
In this review, a complete survey of the traditional uses, chemical constituents (both volatile and nonvolatile), and biological
properties of species from the genera Ballota and Otostegia is provided.
The available information on these genera was collected from
scientific databases and cover from 1911 up to 2018. The following electronic databases were used: PubMed, SciFinder, Science
Direct, Scopus, Web of Science, and Google Scholar.
The search terms used for this review included Ballota, Otostegia,
all the botanical names of the species, both accepted names or
synonyms, phytochemical composition, EOs, traditional uses, activity, pharmacology, and toxicity. No limitations were set for languages. ▶ Table 1 reports the taxa of Ballota and Otostegia investigated so far, their synonyms, and the accepted botanical names.
Rosselli S et al. A Review of …
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Reviews
▶ Table 1 Ballota s. l. and Otostegia s. l. taxa studied so far and their synonymous (accepted botanical name in bold).
Taxa
Synonyms
Ballota acetabulosa (L.) Benth.
Ballota africana (L.) Benth.
Ballota andreuzziana Pamp.
Ballota antalyensis Tezcan & H. Duman
Ballota arabica Hochst. & Steud.
Leucas urticifolia (Vahl) Sm.
Ballota aucheri Boiss.
Otostegia aucheri Boiss.
Ballota cinerea D. Don
Roylea cinerea (D. Don) Baill.; Roylea calycina (Roxb.) Briq.; R. elegans Wall. ex Benth.
Ballota deserti (Noë) Jury, Rejdali & A. J. K.Griffiths
Marrubium deserti (Noë) Coss.
Ballota glandulosissima Hub.-Mor. & Patzak
Ballota hirsuta Benth.
Ballota hispanica (L.) Benth.
Ballota rupestris (Biv.) Vis.
Ballota inaequidens Hub.-Mor. & Patzak
Ballota lanata L.
Panzerina lanata (L.) Soják; Panzeria alaschanica Kuprian.; P. lanata (L.) Bunge
Ballota larendana Boiss. & Heldr.
Ballota latibracteolata P. H. Davis & Doroszenko
Ballota macrodonta Boiss. & Balansa
Ballota nigra L.
B. nigra L. subsp. anatolica P. H.Davis
Ballota nigra subsp. foetida (Vis.) Hayek
Ballota nigra f. uncinata Beg,
Ballota nigra subsp. ruderalis (Sw.) Briq.
Ballota philistaea Bornm.
Ballota pilosa Lour.
Leucas chinensis (Retz.) Sm.; L. mollissima subsp. chinensis (Benth.) Murata
Ballota pseudodictamnus (L.) Benth.
Ballota pseudodictamnus subsp. lycia Hub.-Mor
Ballota rotundifolia K. Koch
Ballota rupestris (Biv.) Vis.
Ballota hispanica (L.) Benth.
Ballota saxatilis Sieber ex C.Presl
Ballota saxatilis subsp. brachyodonta (Boiss.) P. H.Davis &
Doroszenko
Ballota schimperi Benth.
Otostegia fruticosa subsp. schimperi (Benth.) Sebald
Ballota sechmenii Gemici & Leblebici
Ballota undulata (Sieber ex Fresen.) Benth.
Otostegia fruticosa (Forssk.) Schweinf. ex Penzig
Otostegia fruticosa subsp. schimperi (Benth.) Sebald
Otostegia fruticosa subsp. schimperi (Benth.) Sebald
Otostegia integrifolia Benth.
Rydingia integrifolia (Benth.) Scheen & V. A.Albert
Otostegia limbata (Benth.) Boiss.
Rydingia limbata (Benth.) Scheen & V. A.Albert; Ballota limbata Benth.
Otostegia persica (Burm.f.) Boiss.
Rydingia persica (Burm.f.) Scheen & V. A.Albert; Ballota persica (Brum.f.) Benth
Otostegia tomentosa A.Rich.
Traditional Uses
Several plant species belonging to Ballota and Otostegia genera
have been used in traditional medicine of many countries. A summary of their traditional use is presented in ▶ Table 2.
In Europe, the most utilized is, by far, B. nigra, a perennial herb
native to the Mediterranean region and to central Asia, which can
be found throughout Europe. It is also naturalized in Argentina,
Rosselli S et al. A Review of …
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New Zealand, and the eastern United States. Leaves of B. nigra
were used as an antidote for rabid dog bites. It was used in the
Balkanic area as a sedative/tranquilizer in cases of hysteria and hypochondria [31, 32, 37, 38]. It is also used in Italy externally, for
wound-healing properties [33, 36]. Internally, in the Balkans, it is
used as a sedative, a spasmolytic for stomach cramps and aches,
for whooping cough, and to increase bile flow. It is also used to
treat nervousness, upset stomach, nausea, and vomiting [30,
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Ballota cristata P. H.Davis
38]. In Moldova, in the form of enemas and suppositories, it is
used against worm infestation [31]. In northern Spain, it is used
as insecticide and repellent against fleas [39]. In several parts of
Turkey, its subspecies B. nigra L. subsp. anatolica, where it is
known by different vernacular names, has been reported for the
treatment of cold and flu [43], flatulence, and upset stomach
[41] and as antiseptic for wounds, burns, and inflamed skin [40,
42]. B. acetabulosa, known as the Greek horehound, is a compact,
evergreen subshrub, growing to 0.5 m, native to southeast
Greece, Crete, and western Turkey. In Turkey, the infusion of leaves
is used for treatment of stomach ailments, where the leave poultice relieves abdominal pain and hemorrhoids [11, 12].
In the southern part of Africa, the only species present is B. africana, known as Cape horehound or “kattekruie.” It is most common in the more arid, winter rainfall areas of the Cape. Its natural
distribution stretches from the southern part of Namibia down to
the West Coast and Cape Peninsula. Along this wide distribution,
B. africana is usually found along streams and in the shelter of rocks
and bushes. Externally, a leaf compress is applied on sick childrenʼs
feet, on painful legs, inflamed joints, backache, head for headache,
on cheek for toothache, on breasts for mastitis, wash for chilblained hands and feet, wounds, ointment on sores, and as poultice
on boils. Orally, leaf infusion is used for stomach ache, influenza,
fever, asthma, lung, and urinary infections, to treat convulsions in
infants, to wean infants, and as cough syrup [13–15].
Ballota deserti (syn. Marrubium deserti) is a common endemic
species in the northern and central Sahara. In Tunisia, it is employed
in traditional medicine in the form of a decoction as a remedy for
asthma, diabetes, and as a diuretic [25]. The internal usage of this
species has been documented in the central Sahara using the infusion of its leaves for respiratory diseases, fever, colic, colds, cough,
digestive troubles, helminthiasis, and nausea [23, 24]. Another
plant utilized in North Africa (High Atlas, Morocco, and West
Algeria) is B. hirsuta, native to the western Mediterranean region,
mostly abundant in Spain, Portugal, and North Africa. It is very popular with traditional healers (known as “uarimsa,” “touganʼif-zi,” or
“tifziguiyin”) as a cure for many diseases. The poultice of leaves and
roots is used very often to treat subcutaneous lesions (contusion),
rheumatic pains, and heal various wounds. The decoction of flowers
is used externally as an antiseptic or orally against dental caries,
whereas the flower infusion is utilized internally to treat gastrointestinal, gynecological and pediatric diseases [26, 27].
In East Africa (Eritrea, Ethiopia), there are many reports of
some Otostegia species concerning their usage in traditional medicine. The most numerous data are available for O. integrifolia (syn.
R. integrifolia). O. integrifolia, commonly known as Abyssinian rose,
is endemic to Ethiopia, where it is known as “tinjute” (ጥንጁት),
growing in the dry evergreen woodlands regions at altitudes of
1300–2800 m above sea level. It also grows in Eritrea and Yemen.
In northern Ethiopia, it is commonly used to smoke utensils for
sterilization. It is also a ritual custom for a mother to cleanse herself with the smoke on the tenth day after giving birth to a child
before leaving her confinement to resume normal daily activities
[56]. It has been largely employed as an insect repellent against
fleas and mosquitos and as antimalarial [47, 50, 52, 53]. Inhalation
of the smoke of burnt stems and leaves is used against evil eye
[48, 51] and its juice, diluted with water, is drunk for treatment
of stomach ache, vomiting, nausea, diarrhea, and dysentery [46,
51]. In the same geographical area, the juice of O. tomentosa and
O. fruticosa has been similarly used against diarrhea [46], and the
latter also against ascariasis [46] and tonsillitis [48].
O. fruticosa also grows in the Arabic peninsula where the infusion of flowering branches is used as a remedy for sun-stroke [49]
or as an anti-paralytic and for eye diseases [44, 45].
In Pakistan, India and Iran, species belonging to Ballota and Otostegia genera have been largely employed in traditional medicine.
B. arabica (syn. Leucas urticifolia (Vahl) Sm.) is an annual herb
distributed in the Punjab, Baluchistan, Sindh, and Rajputana
desert of Pakistan. In Baluchistan, where it is known as “kubo” or
“goma,” the plant is used as a cure for fever. Furthermore, the decoction of the leaves and apical shoots is used as an abortifacient
up to 3 mo of pregnancy. Infusions of the flowers are used to treat
skin diseases. The plant is also used for the treatment of diarrhea,
dysentery, uterine hemorrhages, dropsy, gravel, cystitis, calculus,
bronchial catarrh, skin diseases, fever, and various types of mental
disorders [16]. The decoction of leaves, roots and flowers of
B. aucheri is topically employed in both Pakistan and Iran as hair
tonic, for strengthening gums, dental cleaning and brightness,
and prevention of hair loss [17, 18]. While in Baluchistan, Iran,
the decoction of leaves and flowers of O. persica (“golder”) is
drunk for treatment of diabetes, rheumatism, cardiac distress,
palpitation, hypertension, cold, hyper lipidemia, gastric discomfort, headache, and as parasite repellent, sedative, laxative, carminative, and antipyretic [17]. In Pakistan, the largest number of
ethno-pharmacological reports involve O. limbata. In fact, it is extensively utilized by traditional practitioners against several ailments since it possesses antispasmodic, antiulcer, antidepressant,
sedative, and anxiolytic properties [68]. O. limbata is consumed
for the treatment of childrenʼs gum problems and for remedial
purposes in cases of ophthalmia [57–59, 61, 63]. Local, fresh
leaves of O. limbata are crushed and then grounded and mixed
with water to make the extract which is also used to cure eye infections. Due to its antiseptic and antibacterial properties [65],
powder of dried leaves is mixed with butter and layered on
wounds and boils in both humans and animals [59, 65, 69]. Dried
plant powder is also utilized against jaundice [61, 63].
Ballota cinerea D. Don is vernacularly known as Karui, Titpatti,
or Patkarru. WP parts are widely used as folk medicine in India
and Nepal. Shoots are crushed and eaten with salt to strengthen
the liver by local villagers. Young shoots are used as insect repellent for cattle during rainy season. Leaves and shoot extraction are
used in scabs and other skin infections. AP are widely used to treat
malaria and various liver disorders like jaundice, liver debility, and
fever [20, 21].
The traditional uses of Ballota and Otostegia species are wide
and sometimes may be directly correlated to the content of some
active class of compounds. Along with diterpenes that characterize these species, flavonoids and phenolic compounds, the latter
ones often occurring as esters moieties, are the main constituents
of the plant extracts and their antibacterial and anti-inflammatory
activities are well documented in literature. They could be responsible for most of the claimed remedies. In the following sections
the metabolic profiles and the biological activities of these plants
have been analyzed.
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Reviews
▶ Table 2 Ethnopharmacological uses of Ballota and Otostegia taxa.
Vernacular
names
Area
B. acetabulosa
boz ot
Aydin, Turkey
stomach ailments, abdominal pain
[11]
Balikesir, Turkey
hemorrhoid treatment
[12]
kattekruid, oulap
Namaqualand,
South Africa
stomach ache, headache, backache, wounds, pediatric, coughs and bronchitis,
chest ailments, toothache, burning feet, earache, convulsions, weaning, chilblained hands and feet, mastitis
[13]
kattekruid
South Africa
fever, cough, asthma, lung infections, influenza, insomnia, stress
[14, 15]
B. arabica
kubo, goma
Baluchistan, Pakistan
abortifacient, astringent, stimulant, hemostatic, anthelmintic, diuretic
[16]
B. aucheri
golder
Baluchistan, Iran
hair tonic, strengthening gums, dental cleaning and brightness,
prevention of hair loss
[17]
chashing
Gilgit Baltistan, Pakistan
hair tonic, dental cleaning
[18]
B. cinerea
kori
Himachal Pradesh, India
stomachache, analgesic
[19]
karui
Uttarakhand, India
fever, jaundice, skin disease, malaria and most prominently in diabetes
[20, 21]
karui, titpati,
patkarru
Nepal, Kashmir
fever, jaundice, scabs, skin disease, malaria, insect repellent
[22]
B. deserti
telheret, meriout
Central Sahara
respiratory diseases, fever, colics, colds, cough, digestive troubles,
helminthiasis, nausea
[23, 24]
Tunisia
asthma, diabetes, diuretic
[25]
B. hirsuta
uarimsa, touganʼif-zi, tifziguiyin
High Atlas, Morocco
general health, gastrointestinal, gynecological, pediatric
[26]
West Algeria
contusion, injuries and rheumatic pain
[27]
Mongolia
treatment of pelvic inflammation and chronic pelvic inflammation, edema,
irregular menstruation, dysmenorrheal, amenorrhea, nephritis
[28]
B. africana
B. lanata
gang gaʼ chung
B. nigra
crna kopriva
erbo moro
B. nigra
L. subsp.
anatolica
Use
Ref
Tibet
stomach, intestinal, and gynecological diseases
[29]
Sharr Mt., Macedonia
digestive
[30]
Moldova
sedative, antispasmodic stimulant, vermifuge
[31]
Northeast BosniaHerzegovina
nervous system disorders, sedation
[32]
Lucca, Italy
against wounds and sprains
[33]
Mediterranean Area
skin disorders, sore throat in horses
[34]
bar qene
Albanians, North
Basilicata, Italy
diuretic, hemostatic
[35, 36]
crna kopriva
Bosnia-Herzegovina
hysteria
[37]
Jadovnik Mt., Serbia
remedy for upset stomach, nausea, and vomiting; symptomatic, treatment of
nervous disorders, sleep disorders, coughs, inflammation, gout
[38]
malrubio negro
North Spain
insecticides and repellents against fleas
[39]
leylimkara
Mersin, Turkey
antiseptic for wounds, to treat inflamed sore in armpit or foot
[40]
elkurtaran
Taurus Mt., Turkey
to treat flatulence and stomach upset
[41]
pemberenkli,
oğul otu, arı oto
Gönen, Turkey
burns, wounds, headache
[42]
grip otu
O. fruticosa
Kırklareli, Turkey
cold, flu
[43]
Yemen
anti-paralytic and for eye diseases
[44, 45]
North Ethiopia
diarrhea
[46]
sasa
Tigray, Ethiopia
repellent of mosquitos
[47]
geram tungut
Central Ethiopia
tonsillitis
[48]
shakab, sharm
Saudi Arabia
remedy for sun-stroke
[49]
cont.
Rosselli S et al. A Review of …
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Species
Reviews
Species
Vernacular
names
Area
Use
Ref
O. integrifolia
cheindog
Eritrea
against fleas and mosquitos
[50]
tinjute
Ethiopia
stomach-ache, evil eye, fever
[51]
O. limbata
O. persica
tinjute
Ethiopia
repellent of mosquito and house fly, antimalarial
[52, 53]
tinjute
Ethiopia
Type 2 Diabetes Mellitus
[54]
chiendog
Tigray, Ethiopia
ectoparasites in livestock
[55]
chiendog
Tigray, Ethiopia
repellent of mosquitos
[47]
tungut
Central Ethiopia
evil eye
[48]
North Ethiopia
vomiting, nausea, diarrhea, dysentery
[46]
North Ethiopia
sterilization, ritual custom
[56]
bui, phut kanda
Northwest Pakistan
treatment of childrenʼs gums and for ophthalmia in men, boils, wound, scabies
[57–59]
pishkand
Battagram, Pakistan
jaundice
[60, 61]
spin azghay
Malakand, Pakistan
dental problems, wounds, cuts, narcotic, tonic, anticancer and goiter
[62]
bui
Punjab, Pakistan
treatment of childrenʼs gums and for opthalmia in man
[63]
sassa
Chon. Karak, Pakistan
treatment of childrenʼs gums and for opthalmia in man
[61]
chitta jand
Jhelum, Pakistan
acidity
[64]
chittakanda
Azad Jammu and Kashmir,
Pakistan
antiseptic, antibacterial, wound healing, ophthalmia, gum diseases
[65]
spin azghay
Dir lower, Pakistan
hypertension
[66]
jand
Azad Kashmir, Pakistan
used to improve eye vision
[67]
Abottabad, Cherat,
Mardan, Malakand, Kohat,
Pakistan
antiulcer, antispasmodic, antidepressant, opthalmia and gums diseases
[68]
koribooti
Himalaya
wound healing
[69]
golder
Baluchistan, Iran
diabetes, rheumatism, cardiac distress, reducing palpitation, hypertension,
laxative, carminative, antipyretic, cold, hyper lipidemia, gastric discomfort,
parasite repellent, sedative, headache
[17]
North Ethiopia
ascariasis, diarrhea
[46]
O. tomentosa
Phytochemicals
Diterpenoids
Seventy-five diterpenes (▶ Figs. 1–3) were isolated and characterized both by their AP and roots of taxa of genus Ballota and Otostegia, and their presence is summarized in ▶ Table 3 (labdane diterpenoids) and ▶ Table 4 (other diterpenoids). Apart from 7αacetoxyroyleanone (73) and coleon A (74), belonging to abietane
diterpenoids, and 7,8β-epoxymomilactone-A (75), belonging to
pimarane diterpenoids, 3 main carbon-skeletons occur: labdane,
hispanane, and clerodane.
The labdane diterpenoids (1–50) (▶ Figs. 1 and 2) are characterized by some interesting structural features. They all belong to
a normal labdane stereochemical series, although Gray et al. [118]
claimed, based on the optical rotation, that compound 27 had an
ent-labdane skeleton. The C-11-C-16 fragment, never carrying an
oxygenated function on C-11 and C-12, can occur with different
substructures. The most common one involves C-13/C-16 in a furane ring that, in a few cases, is oxidized to γ-lactone (6, 7, 13–16,
32, 49). In almost all of the remaining labdanes, C-13 is involved
in the formation of a spiro structure including C-9. By NOE correlations between H-16 and Me-17, it has been shown that all of
them belong to the 13R stereochemical series.
The decalin moiety contains some constant functional features: the decalin junction is always trans and the methyl groups
(C-17) in position C-8; when it is not present, a C-8/C‑9 double
bond is always α-orientated. In the majority of the structures, C6 and C-7 show oxygenated functions and methyl 18 is devoid of
functionalization.
Hispanane-type diterpenoids (▶ Fig. 3) are a scarce group of
natural diterpenoids that exhibits a 6/7/6 tricylic system featured
with a 7-membered carbon ring.
To our knowledge, apart from hispaninic acid (51) and hispanonic acid (52), isolated from B. hispanica [104, 105], limbatenolides A (54), B (55), D (57), E (58) [107, 109], and limbetazulone
(53) [106], isolated from O. limbata and limbatenolide C (56), isolated both from O. limbata [107] and O. persica [108], only 5 other
natural hispananes have been characterized up until now: methyl
verticoate (from Sciadopitys verticillata (Thunb.) Seibold & Zucc.)
[119], salviatalin A [120], salviadigitoside A [120] and salviatalin
A 19-O-β-glucoside [121] (from Salvia digitaloides Diels), and
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▶ Table 2 Continued
viburnumoside (from Viburnum cylindricum Buchanan-Hamilton
ex D. Don) [122].
With the exception of viburnumoside, shown to have an ent absolute configuration (β-H 5 and α-CH3 20) [122], the absolute
configurations of any of the other hispananes have been not determined. In this review, we will report the configuration depicted
in the original papers (α-H 5 and β-CH3 20). The plausible biosynthetic pathway was speculated as a pimarane [121] or labdane
way [123].
Clerodane diterpenods (▶ Fig. 3) showed, differently from labdanes, both a trans junction and a cis junction of the decalin moiety (64–66). Apart from ballodiolic acid (62) and ballodiolic acid A
(63), all the other compounds showed the C-13/C-16 as furane
ring (67, 68) or γ-lactone. Common features to all compounds
are the absence of functionalizations at C-1, C-2, C-7, C-11, C12, Me-17, Me-19, and Me-20 and the presence of a carboxylic acid on C-18 that, in some cases, is lactonized with the hydroxyl
group on C-6 (59, 61, 63, 64, 67–70). In ▶ Table 5, all of the diterpenes are listed, according to their skeleton, in alphabetical order along with their 13C NMR spectra, when available.
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▶ Fig. 2 Structures of ladbane diterpenes.
Flavonoids
In the extensive bibliographic search undertaken, a total of 91 different flavonoids were identified from 22 taxa belonging to Ballota
genus and 3 taxa belonging to Otostegia genus.
The structures of the sugar and acyl groups occurring in the
secondary metabolites are shown in ▶ Fig. 4 and the formula of
all compounds are depicted in ▶ Figs. 5–10. The reported compounds encompass flavones (23 compounds; ▶ Fig. 5), flavonols
(13 compounds; ▶ Fig. 6), flavonoid glycosides (24 compounds;
▶ Fig. 7) flavonoid acyl derivatives (20 compounds; ▶ Fig. 8), Cglycosyl-flavonoids (4 compounds; ▶ Fig. 9), flavanones derivatives (4 compounds; ▶ Fig. 10), and flavanols (4 compounds;
▶ Fig. 10).
▶ Tables 6–8 contain all the flavonoids with their semi-systematic or trivial names, and the genera and species, ordered alphabetically, from which the compounds have been isolated. The
most common compounds are apigenin-7-O-β-D-glucopyranoside (112) (9 taxa), ladanein (79) (8 taxa), apigenin (75) (6 taxa),
luteolin-7-O-β-D-glucopyranoside (116) (6 taxa), and rutin (124)
(6 taxa).
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▶ Fig. 1 Structures of ladbane diterpenes.
the enzyme butyrylcholinesterase. The unusual oxygenated pattern of the flavonoid moiety of leufolin B (153), devoid of hydroxyl
group at C-5 [171], is noteworthy.
From the n-BuOH extract of the AP of Panzeria alaschanica
Kuprian. (syn. B. lanata L.), 2 new flavone C-glycosides, named
panzeroside A (156) and B (157), were isolated. The 2 new compounds demonstrated significant and dose-dependent analgesic
and anti-inflammatory effects [173].
The MeOH extract of the roots of O. limbata was subjected to
several chromatographic separations to give 4 new poly-glycosyl
derivatives of kaempferol: compounds 135, 153, 154, and 155,
the last 3 also carrying p-coumaroyl groups. Their rather complex
structures were elucidated by extensive 1D and 2D NMR [167,
172].
Other metabolites
▶ Fig. 3 Structures of hispanane, clerodane, abietane, and pimarane
diterpenes.
Flavonoid glycosides, described in 24 reports, account for the
vast majority of the 91 total flavonoid reports published so far, followed by flavones (23 reports). Flavonoid coumaroyl glycosides,
present in 18 reports (compounds 136–141, 143–150, 152–
155, 163), have a peculiar chemotaxonomical significance and
are generally considered valuable markers in the Labiatae family
[137].
Although the majority of the flavonoids identified had already
been detected in other genera of several families, some were
identified for the first time.
From the AP of Ballota acetabulosa, 5 flavonoids were isolated
(112, 120, 138, 145, and 146). Compound 146 is a new natural
flavonoid characterized as the cis isomer of chrysoeriol-7-O-β(3′′-p-coumaroyl)glucopyranoside. The trans isomer 145 (co-occurring in the same species) was previously described from other
species belonging to the Lamiaceae family [161].
The new flavonoid coumaroyl glucosides leufolins A (163) and
B (152) were isolated from the EtOAc soluble fraction of the WPs
of L. urticifolia (syn. B. arabica). Their structures were elucidated
on the basis of extensive analysis of 1D and 2D NMR spectral data.
Both compounds exhibited significant inhibitory potential against
Apart from diterpenoids and flavonoids, several other metabolites
have been identified in Ballota and Otostegia taxa: tritepenoids,
steroids (▶ Fig. 11), carboxylic acids (▶ Fig. 12), carotenoids
(▶ Fig. 13, Table 9), nitrogen containing compounds (▶ Fig. 13),
phenylpropanoids, and miscellaneous (▶ Fig. 14, Table 10).
The first study on Ballota and Otostegia genera was carried out
in 1911 by Piault [197], which isolated the tetrasaccharide stachyose from the roots of B. nigra subsp. foetida (237). The following report dates 1934 when, from the same species, Balansard
isolated choline (213) and stachydrine (217) [191].
Phenylpropanoids (218–227) occur within 10 compounds and,
apart from forsythoside B (223) and verbascoside (227), are
present in several species. The main source of this class of compounds is B. nigra from which ballotetroside (221), a new derivative, was isolated [194].
Triterpenoids (10 compounds) and steroids (8 compounds) are
represented by rather common metabolites, although there are
some exceptions. For example, moronic acid (173) was isolated
for the first time in B. cinerea [178], and the new steroid leucisterol (179), as well as the new peroxy acid urticic acid (206), were
isolated from the chloroform soluble fraction of the WP of B. arabica (syn. L. urticifolia). Leucisterol (179) showed potent inhibitory
activity against butyrylcholinesterase enzyme [181]. Recently, the
new, structurally quite complex, bacteriohopane-type derivative
178 was isolated from B. cinerea (syn. Roylea cinerea (D. Don)
Baill.) [182]. In the same work, the β-lactam cinerealactam E
(214) [88] was also detected. Both compounds were shown to
have a significant effect on the decline in blood glucose levels supporting the role of B. cinerea in Ayurvedic medicine for diabetes.
In ▶ Table 11, the occurrence of all of the metabolites in the
single taxa is summarized. For some common compounds, whose
structures have not been depicted in this review, the trivial name
is reported.
EOs
The chemical composition of EOs obtained from 21 species
among Ballota and Otostegia taxa has been investigated. They are
mainly distributed in the Mediterranean area, whereas the Otostegia species are almost totally distributed in western Asia and Ballota lanata, syn. Panzeria (Panzerina) lanata, found in eastern Asia
(Siberia and Mongolia). The major compounds (> 3 %) occurring
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Reviews
No
Names
Taxa
1
7α-acetoxymarrubiin
B. nigra [70]
2
6-acetyl-marrubenol
B. deserti [24]
3
19-acetyl-marrubenol
B. deserti [24]
4
balloaucherolide
B. aucheri [71]
5
ballonigrin
B. acetabulosa, B. antalyensis, B. cristata, B. larendana, B. saxatilis subsp. brachyodonta [72, 73], B. aucheri [74], B. inaequidens [72, 73, 75, 76], B. lanata [77],
B. nigra [70], B. nigra subsp. foetida [72, 73, 78], B. pseudodictamnus [79],
B. rupestris [70, 78], B. saxatilis [72, 73, 80], B. undulata [81], O. fruticosa [82]
6
ballonigrin lactone A
O. limbata [83]
7
ballonigrin lactone B
O. limbata [83]
8
ballonigrinone
B. rupestris [70, 78], B. undulata [81]
9
ballotenol
B. nigra subsp. foetida [84]
10
ballotinone
B. aucheri [71], B. nigra subsp. foetida [85], B. undulata [81]
11
calyenone
B. cinerea [86]
12
calyone
B. cinerea [86, 87]
13
cinereanoid A
B. cinerea [87]
14
cinereanoid B
B. cinerea [87]
15
cinereanoid C
B. cinerea [88]
16
cinereanoid D
B. cinerea [88]
17
cyllenin A
B. deserti [89, 90]
18
dehydrohispanolone (hispanone)
B. acetabulosa, B. antalyensis, B. cristata, B. larendana, B. latibracteolata, B macrodonta, B. nigra subsp. uncinata, B. pseudodictamnus subsp. lycia, B. rotundifolia,
B. saxatilis subsp. brachyodonta [72, 73], B. saxatilis [72, 73, 80], B. undulata [81],
O. fruticosa [82]
19
6-dehydroxy-19-acetyl-marrubenol
B. deserti [24]
20
desertin
B. deserti [89, 90]
21
15-epi-cyllenin A
B. deserti [89, 90]
22
15-epi-leopersin C
O. fruticosa [82]
23
15-epi-otostegin B
O. fruticosa [82]
24
16-epoxy-9-hydroxylabda-13(16), 14- diene
B. deserti [24]
25
hispanolone
B. acetabulosa, B. cristata, B. pseudodictamnus subsp. lycia, B. rotundifolia,
B. saxatilis subsp. brachyodonta [72, 73], B. africana [91], B. andreuzziana [79],
B. hirsuta [92], B. inaequidens [72, 73, 75, 76], B. saxatilis [72, 73, 80]
26
3β-hydroxyballotinone
B. undulata [81]
27
6β-hydroxy-15,16-epoxy-labda-8,13(16),14-trien-7-one
B. aucheri [74]
28
6β-hydroxy-15α-methoxy-9α,13,15,16-bis-epoxylabd-7-one
B. aucheri [71]
29
6β-hydroxy-15β-methoxy-9α,13,15,16-bis-epoxylabd-7-one
B. aucheri [71]
30
6β-hydroxy-15β-ethoxy-9α,13,15,16-bis-epoxylabd-7-one
B. aucheri [71]
31
9α-hydroxy-6,9 : 15,16-diepoxy-13(16),14-labdadien-7-one
B. aucheri [74]
32
13-hydroxyballonigrolide
B. lanata [77], B. nigra [93, 94]
33
18-hydroxyballonigrin
B. acetabulosa [95], B. pseudodictamnus [79], B. saxatilis [96]
34
leoheterin
B. aucheri [71, 74, 97], O. fruticosa [82, 98]
35
leopersin C
O. fruticosa [82]
36
marrubenol
B. pseudodictamnus [79]
37
marrubiin
B. deserti [89, 90], B. nigra subsp. foetida [85, 99]
38
marrulactone
B. deserti [89, 90]
39
marrulibacétal
B. deserti [89, 90]
40
marrulibacétal A
B. deserti [90]
continued
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▶ Table 3 Distribution of labdane diterpenes in Ballota and Otostegia taxa.
Reviews
▶ Table 3 Continued
Names
Taxa
41
otostegin A
O. fruticosa [82]
42
otostegin B
O. fruticosa [82]
43
otostegindiol
O. integrifolia [100, 101]
44
persianone
B. aucheri [74]
45
precalyone
B. cinerea [86]
46
preleoheterin
B. aucheri [71, 97], O. fruticosa [82]
47
preleosibirin
B. nigra subsp. foetida [102]
48
preotostegindiol
O. integrifolia [100]
49
rupestralic acid
B. rupestris [103]
50
vulgarol
O. fruticosa [82]
in the chemical composition of the EOs are reported in ▶ Table
12.
All papers are quite recent, they have been published starting
in 2002, except for one [224], published in 1995.
The first published paper concerns the analysis of an Egyptian
O. fruticosa [224] species, cultivated in the station of faculty of
agriculture of Mansoura University, containing mainly monoterpenes with a high level of thymol (43.7 %). A recent re-investigation of the same species collected wild in the Sinai region showed
a composition strongly dominated by sesquiterpenes with the
caryophyllene oxide being the most abundant component
(60.8 %) [175].
For the single species Ballota sechmenii Gemici & Leblebici, only
the relative content of linalool (5.0 %) and its enantiomeric composition, (+)-isomer (26.9 %), (−)-isomer (73.1 %) have been determined [223]. No other component of the EO was reported.
With only a few exceptions, such as B. lanata [29, 206] and
2 B. nigra specimens collected in the Golestan region of Iran
[210] and Ukraine [211], respectively, Ballota species EOs are
mainly composed of sesquiterpenes with caryophyllene, caryophyllene oxide, and germacrene D often identified as main compounds. On the contrary, in B. lanata, monoterpenes are the dominant components, similar to the B. nigra of Golestan. The analysis
of EOs of different plant parts of Ukrainian B. nigra, showed that
fatty acids are the most relevant compounds with sesquiterpenes
occurring only in the corallas. However, a nonconventional method of EO extraction was applied.
The Otostegia species studied to date shows controversial results. The case of the O. fruticosa, discussed above, and of the
O. michauxii, collected in 2 different locations, are emblematic.
In fact, the O. michauxii from southern Zagros of Iran show caryophyllene oxide as a main compound [225], whereas the one collected in the Fars province of Iran had an equal amount of monoterpenes and sesquiterpenes [226]. In O. integrifolia, the monoterpene α-pinene occurs in 31 % of the oil [56], whereas in some collections of O. persica, in several places of southeast Iran, a clear
trend cannot be observed.
Biological Properties
This section deals with the corpus of scientific evidence related to
the claims of the biological effects of Ballota and Otostegia genus
utilized in traditional medicine (▶ Table 2). The most widespread
usage of the plants is as an aqueous infusion of the drug, which is
normally made from the WP dried. The beneficial effects should
normally be associated with the presence of polar or water-soluble active principles. Indeed, most of the cited literature deals
with the effect of the extract obtained from leaves, stems, roots,
flowers, WPs in polar solvent, such as EtOH, MeOH and water, as
well as mixture of them. However, investigations concerning the
bioactivity of fractions obtained with less polar solvents, such as
choloroform, n-Hex, and EtOAc are also present. In some cases,
isolated individual compounds were assessed for their bioactivity.
In other cases, the EOs are the focus of the research and their
composition is investigated and correlated to the bioactivity observed for that species.
In this report, a selection of the more relevant results, obtained
with rigorous and well-defined methodological approaches, are
taken into consideration. Redundant investigations that report
data concerning the same combinations of plant species and biological targets can often be found in literature, in particular concerning antimicrobial activity.
Antioxidant activity
Many of the effects of Ballota and Otostegia reported in ▶ Table 2
may be related by their general antioxidant activity, which is well
documented in the literature. This activity is generally attributed
to the presence of phenolic compounds that are ubiquitous in
these genera. In a few cases, terpenoidic compounds, in particular
diterpenes, were also identified as the source of antioxidative
properties of the drug. The mechanisms of action may include
oxygenated radicals scavenging, inhibition of the enzymatic peroxidation, etc. Furthermore, the variety of antioxidant activity
evaluation protocols utilized often make it difficult to directly
compare the effects of different species. Nevertheless, the antioxidant activity of many Ballota and Otostegia plants has been interestingly and undoubtedly demonstrated. These findings are
summarized in ▶ Table 13, where for each investigation reviewed
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▶ Table 4 Distribution of other diterpenes in Ballota and Otostegia
taxa.
Hispanane skeleton
51
hispaninic acida
B. hispanica [104, 105]
52
hispanonic acida
B. hispanica [104, 105]
53
limbetazulone
O. limbata [106]
54
limbatenolide A
O. limbata [107]
55
limbatenolide B
O. limbata [107]
56
limbatenolide C
O. limbata [107], O. persica [108]
57
limbatenolide D
O. limbata [109]
limbatenolide E
O. limbata [109]
58
Clerodane skeleton
59
ballatenolide A
O. limbata [107], O. persica [108]
60
ballotenic acid
O. limbata [110]
61
ballotenic acid A
O. limbata [111]
62
ballodiolic acid
O. limbata [110]
63
ballodiolic acid A
O. limbata [111]
64
limbatolide A
O. limbata [112]
65
limbatolide B
O. limbata [112]
66
limbatolide C
O. limbata [112]
67
limbatolide D
O. limbata [113]
68
limbatolide E
O. limbata [113]
69
limbatolide F
O. limbata [114]
70
limbatolide G
O. limbata [114]
71
15-methoxypatagonic acid
O. limbata [107], O. persica [108]
72
patagonic acid
O. limbata [107], O. persica [108]
Abietane skeleton
73
7α-acetoxyroyleanone
B. nigra [115]
74
coleon A
B. cinerea [116]
Pimarane skeleton
75
7,8β-epoxymomilactone-A
B. arabica [117]
peroxides test, and FRAP. The extract significantly reduced the effect of H2O2 in a dose-dependent fashion (50–250 µg/mL).
The direct correlation between the phenolic compounds content is rather general, although some exceptions are also known.
For example, in an investigation of the antioxidant properties of
O. limbata from Pakistan [242], the methanolic extract was subsequently divided in fractions soluble in n-Hex, CHCl3, EtOAc, nBuOH, MeOH, and H2O, and total content in phenolic compounds
and flavonoids was determined. The EtOAc fraction resulted the
one with the highest antioxidant power (EC50 TPPH test 60.9 µg,
total phenolic compounds 1119 mg), even if the higher phenols
content was found in n-Hex (3908 mg, EC50 226.1 µg) and 1-butanol (3037 mg, EC50 96.3 µg).
The antioxidant activity of apigenin-7-O-(6″-O-[E]-coumaroyl)β-glucopyranoside (139), a flavonoid glycoside isolated from the
B. lanata (syn. P. alaschanica) AP collected in China [169], was determined in vivo by evaluating its lipid peroxidation inhibitory activity. A diabetes mellitus–related oxidative stress was induced in
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the species involved is reported together with its provenience, the
extraction mode, and the testing procedure implemented.
As it can be inferred from the analysis of ▶ Table 13, B. nigra
and O. persica are the most studied species. Their antioxidant activity was evaluated in the EO [196, 228, 229], as well as in different polarity fractions (extraction solvents: PE, Ac, EtOAc, MeOH,
EtOH, water) of the extract obtained from leaves, AP, and the
WP. In some cases, a number of individual active compounds were
isolated and identified. The following were purified from leaf extract (water/EtOH 1 : 1) of B. nigra collected in France [236, 237]:
(+)-(E)-caffeoyl-L-malic acid (186), verbascoside (227), forsythoside B (223), arenarioside (220), and ballotetroside (221). On the
other hand, morin (110) and quercetin (100) were isolated from
the bio-guided purification of the methanolic extract of O. persica
[160]. In an interesting study [236], some chemical indicators of
the intracellular inflammatory cascade reaction of the neutrophils
were evaluated: superoxide anion, H2O2, HClO, and OH radical. All
of the compounds were found to be active, inhibiting the development of oxygenated species to various degrees; only ballotertoside (221) was inactive in the superoxide anion and OH radical
tests. In another study [237], the same authors evaluated all
5 molecules for their inhibitory efficacy with respect to the oxidation of low-density lipoproteins (LDL). They were also assessed for
their Cu(II) chelating power, as this is the well-known mechanism
of action of the antioxidant quercetin. None of them were able to
behave as a copper chelating agent. The infusion of B. nigra leaves
from the Czech Republic was shown to possess outstanding antioxidant activity, in particular by DPPH, NO, and superoxide anion
scavenging ability [185]. On the contrary, no OH radical scavenging ability was revealed. In terms of organic acids and polyphenol
content of the infusion, the composition was determined by
HPLC/DAD and HPLC/UV analysis and the authors inferred the correlation between these compounds and the observed antioxidant
activity. The crude methanolic extract of AP of B. hirsuta [234] and
O. limbata [241] were further partitioned in several solvents in order to select phenolic enriched subfractions following the solubility properties of different compounds, the EtOAc fraction being
the most active in both cases: in the DPPH test, the IC50 were
13.53 µg/mL for O. limbata and 70.0 µg/mL for B. hirsuta. On the
contrary, the less active fraction of the extract was the one in
H2O for B. nigra (129.5 µg/mL) and the one obtained in CHCl3 for
B. hirsuta (260 µg/mL). A significant difference in the antioxidant
power of different solvent fractions was found for O. persica collected in Iran [158]. The fraction soluble in MeOH showed LPO inhibition in the NH4SCN test comparable to that of α-tocopherol
(95.87 %). On the other hand, the fractions soluble in n-Hex and
CHCl3 were poorly active (2.5 and 1.9 %, respectively). These variations in the antioxidant activity, evidenced by different partition
solvents, can be related to the affinity of the active metabolites
(poly-phenols and flavonoids) to these solvents.
The relation between the antioxidant power of O. persica extract (AP, 70 % MeOH) and the protective effect against the damages caused by the oxidative stress on the endothelium cells, was
investigated in vitro on a human cell line: the umbilical vein endothelial cells [244]. No toxicity was revealed up to 250 µg/mL of extract. The oxidative effects were induced by H2O2 and evaluated
by the cell viability essay (MTT), intracellular and extracellular total
13
CNMR data of diterpenes from Ballota and Otostegia taxa.
Skeleton
numbering
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
124.6
110.7
138.8
143.2
17
18
19
20
1′
2′
Ref.
183.1
22.6
171.0
21.0
[70]
Labdane
skeleton
33.4
17.5
29.3
43.7
46.0
75.8
70.6
38.8
79.2
39.1
28.4
18.4
13.9
22.8
1
7α-acetoxymarrubiin
2
6-acetylmarrubenol
Not reported in literature
3
19-acetylmarrubenol
Not reported in literature
4
balloaucherolide
37.2
17.2
32.3
35.7 124.3 143.1 181.7 140.5
165.8
43.8
23.8
29.4
127.4
110.5
140.5
143.1
11.6
28.1
27.9
27.6
5
ballonigrin
30.3
17.8
27.7
42.0
49.5
75.5 193.2 131.2
166.7
36.7
30.0
24.6
123.7
110.5
143.1
138.8
11.9
24.5
180.1
28.0
6
ballonigrin
lactone A
28.1
21.9
27.6
42.2
49.3
78.8 194.1 135.7
165.3
39.1
29.9
24.6
139.1
141.3
100.9
170.6
17.4
26.7
176.4
22.4
7
ballonigrin
lactone B
26.1
21.3
28.2
45.9
48.3
80.1 197.1 132.7
162.4
38.5
31.2
22.9
136.5
145.9
74.4
172.1
17.6
27.1
178.5
23.1
[83]
8
ballonigrinone
30.1
34.0 203.4
52.1
50.2
74.5 191.3 132.6
163.7
36.1
30.3
24.1
123.4
110.5
143.3
138.8
12.1
21.6
172.1
24.2
[81]
[84]
[71]
[81]
56.2
[83]
Rosselli S et al. A Review of …
9
ballotenol
35.5
18.9
39.3
44.2
51.4
74.9 213.0
46.0
82.9
40.1
43.5
22.0
126.0
111.4
143.3
138.8
8.7
27.8
67.0
20.1
10
ballotinone
28.8
17.8
28.8
41.6
44.6
75.6 209.4
51.4
77.7
40.6
37.8
18.1
124.2
110.6
143.1
138.7
15.7
26.3
180.3
17.9
11
calyenone
34.5
22.9
76.8
36.6
44.5
30.1 199.3 166.1
130.6
40.4
29.4
24.3
124,3
110.5
142.3
138.6
18.0
27.0
21.3
11.5
170.2
21.1
[86]
12
calyone
25.6
22.7
77.3
37.0
41.1
38.5 211.4
51.0
81.6
43.0
34.7
21.5
124.6
110.6
143.1
138.5
8.3
27.6
21.2
16.0
170.6
21.5
[87]
13
cinereanoid A
30.4
23.8
78.5
37.7
46.2
35.5 201.9 131.9
168.3
42.1
27.8
27.6
176.3
118.2
173.6
100.9
11.6
27.6
21.7
18.2
172.3
21.1
[87]
14
cinereanoid B
26.8
23.8
79.2
38.1
42.3
39.5 214.5
51.9
82.5
44.5
32.3
25.6
172.6
117.8
173.7
101.2
8.6
28.2
21.9
16.8
172.6
21.1
[87]
15
cinereanoid C
30.4
23.8
78.5
37.7
46.2
35.5 202.0 132.0
168.5
42.1
25.6
28.5
137.4
147.0
99.2
173.8
11.8
27.6
21.8
18.2
172.4
21.1
[88]
16
cinereanoid D
35.5
69.2
77.6
38.9
45.6
35.2 201.3 132.3
166.8
43.0
27.5
27.5
170.9
118.4
173.4
100.9
11.7
27.8
21.4
19.4
172.1
21.1
17
cyllenin A
28.4
17.3
27.6
43.6
45.8
75.7
31.2
91.3
38.5
29.1
34.7
89.5
46.0
98.7
76.1
16.9
22.6
183.6
23.0
[124]
18
dehydrohispanolone (hispanone)
35.8
18.6
41.3
33.1
50.2
35.2 200.3 130.3
167.0
40.9
30.2
24.2
124.5
110.5
143.0
138.6
11.4
32.5
21.3
18.1
[125]
19
6-dehydroxy19-acetylmarrubenol
31.6
18.2
35.7
36.9
47.5
22.6
79.6
43.0
35.0
22.6
125.5
110.8
142.8
138.4
16.2
26.8
67.1
16.9
171.4
20.9
56.4
55.1
30.9
31.2
36.6
20
desertin
28.4
18.2
28.3
43.9
45.0
76.3
31.6
32.5
75.3
40.1
28.2
27.4
81.2
80.2
110.8
108.6
16.8
23.0
183.9
22.2
21
15-epi-cyllenin A
28.3
17.5
27.7
43.6
45.8
75.7
30.9
31.2
90.0
38.4
28.9
37.2
89.5
48.1
98.7
76.4
16.9
22.4
183.3
23.2
77.4
47.0
93.4
48.3
29.5
38.8
91.0
47.9
99.0
78.4
13.3
22.2
32.4
19.7
76.0 204.5
45.5
98.2
43.9
30.1
38.8
90.6
42.1
101.2
71.0
9.5
33.1
24.9
20.3
22
15-epi-leopersin C
32.7
18.3
42.4
32.4
57.2 212.0
23
15-epi-otostegin B
34.8
19.1
44.1
35.2
49.1
Planta Med
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
[81]
[88]
[24]
[89]
[124]
[126]
169.8
21.8
[82]
cont.
Reviews
▶ Table 5
Rosselli S et al. A Review of …
▶ Table 5 Continued
Skeleton
numbering
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
1′
2′
Ref.
Not reported in literature
Planta Med
24
16-epoxy-9-hydroxylabda13(16), 14- diene
25
hispanolone
31.9
18.5
41.3
33.6
46.4
39.2 211.9
50.9
81.8
43.3
34.7
21.5
124.8
110.7
143.0
138.6
8.2
33.1
21.4
16.2
[127]
26
3β-hydroxyballotinone
27.8
28.2
73.5
44.1
49.9
75.9 208.3
51.6
77.5
40.8
37.8
18.0
124.0
110.5
143.3
138.8
15.8
23.2
180.0
17.7
[81]
27
6β-hydroxy15,16-epoxy-labda-8,13(16),14trien-7-one
37.4
18.6
43.2
33.9
53.2
70.7 199.4 128.2
169.8
41.1
30.6
24.2
124.3
110.4
142.9
138.5
11.6
32.4
23.9
18.6
[74]
28
6β-hydroxy-15α-methoxy-9α,13,15,16-bisepoxylabd-7-one
Not reported in literature
29
6β-hydroxy-15β-methoxy-9α,13,15,16-bisepoxylabd-7-one
Not reported in literature
30
6β-hydroxy-15β-ethoxy-9α,13,15,16-bisepoxylabd-7-one
Not reported in literature
31
9α-hydroxy6,9 : 15,16-diepoxy-13(16),14labdadien-7-one
31.8
19.3
41.3
32.3
55.6
81.8 214.8
32.4
108.0
48.9
36.0
18.7
124.8
110.8
142.8
138.6
7.5
33.8
22.0
16.8
[74]
32
13-hydroxyballonigrolide
30.2
18.1
28.1
42.1
49.3
76.1 193.6 131.1
167.1
37.0
24.3
37.5
76.4
42.5
180.2
79.1
24.5
27.9
180.9
12.1
[77]
33
18-hydroxyballonigrin
30.2
17.7
22.5
48.8
45.6
77.3 193.5 131.2
166.6
36.4
29.4
24.2
123.8
110.6
143.2
138.8
29.0
67.5
180.1
12.1
[95]
34
leoheterin
31.6
18.1
42.0
32.2
55.9 212.0
77.1
47.6
77.2
49.0
34.2
21.2
124.7
110.6
143.2
138.6
12.4
32.6
22.2
18.0
[74]
35
leopersin C
32.3
18.2
42.4
32.4
57.0 211.5
77.4
46.8
92.1
48.2
29.1
35.9
90.7
46.4
99.0
76.9
13.1
22.1
32.4
19.7
[126]
36
marrubenol
33.8
18.5
40.7
38.9
49.3
38.9
31.1
77.0
43.4
34.9
21.5
125.4
110.8
142.8
138.5
16.2
27.8
69.1
19.6
[128]
37
marrubiin
35.1
18.1
28.5
43.8
44.8
76.3
31.4
32.3
75.6
39.7
28.3
21.0
125.1
110.7
142.9
138.5
38
marrulactone
28.8
18.4
28.5
44.1
45.0
75.7
31.7
32.4
88.3
39.0
34.5
20.5
34.4
172.1
39
marrulibacétal
27.9
17.9
28.2
43.9
44.7
76.5
32.3
33.7
80.4
41.0
21.1
29.6
75.6
78.5
108.7
40
marrulibacétal A
27.8
17.9
28.2
43.9
44.6
76.6
32.3
33.5
80.3
40.9
20.7
30.0
75.8
78.6
109.8
41
otostegin A
34.4
28.7
43.7
34.9
50.2
77.1 204.2
46.7
96.6
43.1
30.4
37.6
93.7
106.9
148.2
42
otostegin B
34.9
19.1
44.3
35.2
49.3
76.1 204.5
45.8
98.1
43.8
30.4
38.9
90.7
42.2
101.2
71.0
9.5
33.1
43
otostegindiol
25.1
25.6
76.3
43.2
39.8
21.6
37.1
77.5
37.8
35.5
21.9
126.1
111.3
143.2
138.9
16.5
22.6
65.9
31.4
16.6
22.9
184.0
22.3
[85]
16.8
23.1
183.4
22.6
[129]
105.4
19.5
23.2
183.9
22.0
63.9
105.7
19.4
23.2
184.1
22.0
55.5
80.5
9.2
32.6
23.9
29.4
269.4
21.3
24.2
20.3
169.8
21.8
29.0
16.8
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
15.0
[129]
[90]
[82]
[82]
[130]
cont.
Skeleton
numbering
1
2
18.2
3
4
42.3
32.3
5
6
44
persianone
31.5
36.5
18.7
42.2
45
precalyone
38.2
22.7
77.5
46
preleoheterin
42.2
18.3
32.3
32.4
57.1 212.1
47
preleosibirin
48
preotostegindiol
25.1
25.2
76.1
42.4
39.8
21.2
49
rupestralic acid
30.1
18.1
28.1
42.3
49.4
50
vulgarol
36.8
19.0
42.6
33.3
46.9
21.0
7
8
9
57.4 210.7
65.0
50.5
77.0
32.1
58.3 211.3
67.9 128.1
36.9
40.1
10
48.7
11
43.6
12
13
14
15
16
21,5
124.9
110.7
143.0
138.6
17
13.1
18
32.7
19
20
22.3
18.0
21.3
1′
2′
Ref.
[74]
144.4
45.1
29.2
25.4
125.1
110.7
142.8
138.5
16.5
33.1
21.9
50.0
86.0
42.5
29.4
26.4
94.0
107.0
148.3
80.8
17.1
27.1
21.2
9.2
77.2
47.5
93.9
48.1
29.9
37.7
92.1
107.3
148.3
80.9
13.2
32.3
22.3
19.3
[71]
31.6
37.3
93.3
37.7
32.0
35.6
93.0
107.6
147.8
81.5
17.6
22.4
29.5
21.1
[130]
76.1 193.8 131.7
165.6
36.9
24.7
27.3
136.0
146.5
98.5
172.1
24.7
27.4
180.7
12.1
[77]
61.2
39.2
25.8
43.4
140.9
123.4
59.5
16.9
32.3
33.5
21.7
25.2
[82]
38,2 210.2
170.3
21.1
[86]
Not reported in literature
37.8
74.0
Hispanane
skeleton
51
hispaninic acida
36.7
19.4
37.4
43.8
52.9
20.7
34.1 126.2
147.9
40.8
25.0
27.0
151.2
113.6
169.4
158.1
116.5
28.3
177.4
16.9
51.2
[131]
52
hispanonic acida
36.3
19.4
37.4
43.8
53.0
20.1
28.1 134.7
154.0
41.3
27.6
25.0
135.7
112.7
145.8
149.6
183.1
28.2
177.7
16.7
51.2
[131]
53
limbetazulone
34.3
27.5
80.1
42.8
52.2
18.2
27.9 134.3
154.3
40.2
25.1
28.0
135.8
112.8
146.0
149.6
183.1
22.5
64.1
29.9
[106]
54
limbatenolide A
34.2
18.1
27.5
42.8
51.1
80.1
28.0 134.2
154.1
40.1
25.0
27.9
135.6
112.7
145.9
149.1
183.0
22.5
64.1
19.9
[107]
55
limbatenolide B
34.5
18.6
29.6
42.7
51.1
80.1
33.8 125.7
147.9
39.0
24.7
27.0
151.0
113.7
172.0
157.9
116.1
22.4
64.0
20.2
[107]
56
limbatenolide C
37.2
19.5
36.0
43.5
53.0
20.8
35.6 127.5
142.4
40.5
25.2
27.8
130.1
115.1
172.9
143.2
114.9
28.1
182.2
17.2
[107]
57
limbatenolide D
38.4
20.4
32.4
44.1
53.1
83.5
29.2 136.1
152.6
42.3
25.4
28.6
135.9
113.4
144.1
150.6
184.3
25,2
180.1
18.5
[109]
58
limbatenolide E
37.1
20.9
33.0
42.6
51.9
80.3
35.6 127.1
145.9
40.3
24.8
27.2
250.1
114.1
170.6
156.7
118.2
27.0
181.9
19.3
[109]
Clerodane
skeleton
Rosselli S et al. A Review of …
Planta Med
59
ballatenolide A
17.5
27.3 130.1 139.7
39.1
86.1
31.4
38.1
42.3
44.9
36.4
19.9
138.8
141.6
102.5
172.0
15.5
171.0
16.1
19.7
60
ballotenic acid
17.4
27.4 140.5 141.1
37.5
35.7
27.2
36.1
38.7
46.5
36.0
22.6
39.6
29.6
66.4
172.8
15.9
171.0
20.5
18.3
[110]
61
ballotenic acid A
17.8
28.1 134.2 140.1
40.1
84.5
30.9
39.3
42.5
45.7
35.9
23.6
41.2
32.3
70.1
173.2
16.5
172.7
17.8
20.6
[111]
62
ballodiolic acid
17.5
27.4 140.0 141.3
37.5
35.6
27.2
36.1
38.6
46.6
35.8
24.9
39.8
29.7
66.3
61.1
15.9
172.0
20.5
18.4
[110]
63
ballodiolic acid A
18.5
26.4 132.6 138.9
41.1
85.3
32.7
37.5
43.2
46.1
37.3
25.9
40.1
30.5
68.8
63.6
15.5
171.3
16.5
18.1
[111]
64
limbatolide A
19.4
28.5 132.1 140.3
40.5
85.2
30.3
37.5
40.9
45.6
37.8
21.3
139.7
142.3
100.8
173.6
15.9
170.8
31.7
22.5
55.7
65
limbatolide B
18.2
28.3 142.1 139.5
38.2
36.1
27.2
37.1
39.9
45.2
35.7
20.3
133.3
142.3
103.4
173.1
16.3
171.8
32.3
23.1
57.6
66
limbatolide C
18.1
27.3 142.3 139.1
38.5
36.0
26.5
38.3
40.1
45.4
36.9
21.3
136.1
144.4
71.4
173.7
16.8
171.5
33.1
16.8
[112]
67
limbatolide D
18.2
27.1 132.6 140.5
40.6
82.4
32.6
39.1
41.3
45.1
38.2
18.4
131.5
111.3
143.4
137.7
16.6
174.1
18.1
19.3
[113]
68
limbatolide E
30.5
72.3 125.6 139.6
42.3
84.5
33.1
40.5
44.3
46.7
37.1
20.1
130.1
111.7
143.6
140.2
15.8
172.1
19.3
19.8
[113]
69
limbatolide F
20.3
27.4 131.1 140.1
43.0
84.4
32.7
37.5
41.6
47.1
36.6
19.6
133.4
143.4
71.4
173.0
15.8
170.4
18.2
19.0
[114]
70
limbatolide G
19.5
28.3 133.9 141.2
42.4
83.4
33.8
39.3
40.1
46.2
37.8
18.0
135.6
141.4
101.1
171.8
16.1
169.3
17.5
19.5
[114]
cont.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
57.1
[107]
[112]
[112]
Reviews
▶ Table 5 Continued
[133]
[133]
[132]
21.1
[107]
[107]
17.6
110.5
The spectra were recorded as methyl ester derivative.
a
Not reported in literature
7,8β-epoxymomilactone-A
75
38.5
118.4 135.1
74b coleon A(19S)
Pimarane
skeleton
119.5 132.5
coleon A(19R)
74a
35.8
rats with a 7 week treatment of STZ. Afterward, the plasma concentration of malondialdehyde (MDA), co-enzyme Q9, α- and γtocopherol were measured. A normalization in MDA values was
observed in animals treated with 60 mg/kg b. w. of compound
139, while the Q9 and γ-tocopherol level remained comparable
with those of negative controls.
Anti-inflammatory activity
This is mainly attributed to the presence of flavonoids and tannins
in both genera. The bioactivity is generally evaluated in in vivo
models. The aqueous extract of Ballota glandulosissima Hub.Mor. & Patzak leaves collected in Turkey [245] administrated to
rats with carrageenan-induced paw edema (100 mg/kg b. w.) was
able to induce a significant reduction of the edema volume (32 %).
The aerial part aqueous extract of Ballota inaequidens Hub.-Mor. &
Patzak from Turkey [246] showed similar effects by reducing paw
edema in rats in a dose-dependent manner: the volume reduction
coefficient ranged from 58 to 86 % by administrating 50 to
200 mg/kg b. w. per day of extract. This species also showed
significant, positive dose-dependent results in the abdominal
stretching test in mice: 44–91 % reduction by administrating 30–
100 mg/kg b. w. per day of dry extract. A relevant anti-inflamma-
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
24.6
19.8
19.8
23.9
191.2
125.5
154.5
180.6
134.3
120.2
50.0 136.9 152.1 146.9 116.8
134.4
46.1
33.0
7α-acetoxyroyleanone
73
Abietane
skeleton
1
Skeleton
numbering
18.8
17.3
patagonic acid
72
41.0
50.4 137.0 152.4 146.9 116.8
120.3
180.6
154.5
125.4
191.2
23.9
19.8
19.8
18.4
107.1
17.4
169.5
39.1
149.9
24.6
64.5 139.4
46.6
36.2
37.5
27.4 141.2 140.4
35.7
27.2
38.7
36.2
183.7
19.2
150.7
134.9
124.7
143.5
185.4
70.2
24.1
19.7
174.3
15.9
19.9
21.6
172.5
20.5
33.0
18.2
18.5
57.0
18.1
20.5
171.3
15.5
172.2
102.5
143.0
134.0
19.3
36.3
46.7
38.8
36.3
27.4
35.7
37.5
27.2 141.3 140.4
17.4
15-methoxypatagonic acid
71
43.0
Ref.
2′
1′
20
19
18
17
16
15
14
13
12
11
10
9
8
7
6
5
4
3
Planta Med
2
Rosselli S et al. A Review of …
▶ Table 5 Continued
▶ Fig. 4 Structures of sugars and acyl moieties.
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Reviews
▶ Fig. 7 Structures of glycosyl flavonoids.
▶ Fig. 5 Structures of flavones.
▶ Fig. 6 Structures of flavonols.
tory activity was also demonstrated in the methanolic extract of
the AP of B. pseudodictamnus. This species is included in a comparative study on the anti-inflammatory activity of endemic flora
from Libya [247]. In the mice paw edema test, a single dose of
500 mg/kg b. w. reduced the edema volume by 51 %.
The same animal model was employed in the evaluation of the
anti-inflammatory activity of the crude extract of the aerial part of
O. persica [166], as well as the fractions soluble in organic solvents
of different polarities (PE, CHCl3, EtOAc, n-BuOH, MeOH). The analgesic activities were also investigated. Both the fraction in BuOH
and in MeOH were able to reduce the edema volume, the last one
▶ Fig. 8 Structures of acyl flavonoids.
showing an efficacy comparable to that of indomethacin. Furthermore, the MeOH fraction showed analgesic activity with EC50 of
85.9 mg/kg b. w. Two active compounds were isolated from the
methanolic fraction: vicenin-2 (159) and isorhamnetin-3-O-β-Dglucopyranoside (128).
Rosselli S et al. A Review of …
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▶ Fig. 9 Structures of C-glycosyl flavones.
The extract of B. deserti (Algeria) was obtained from AP with PE,
dichloromethane, and MeOH. Their anti-inflammatory activity
was assessed, once again with the paw edema model, using
Wister albino rats [248]. The edema volume was reduced by
85.5 % by a dose of 200 mg/kg b.w after 3 h of the MeOH extract,
while acute toxicity signs were absent until 5000 mg/kg b. w. The
lowest, but still significant effect, was obtained in another study
[248] with the aqueous extract of the same taxa: edema volume
was reduced after 3 h from 11 to 44 % at variable doses from 250
to 1000 mg/kg b. w.
The EtOAc extract of the aerial part of B. lanata from China
[144] was investigated for its potential anti-inflammatory activity
in 2 animal models: the paw edema induced by carrageenan and
egg albumin in rats. The effect of edema reduction after treatment with 100 to 400 mg/kg b. w. of extract was dose-dependent:
at the highest dose, there was an effect statistically comparable
with the positive reference luteolin (85). Another study reported
the isolation of apigenin-7-O-β-D-(6′′-E-p-coumaroyl)glucopyranoside (139), apigenin-7-O-β-D-(2″,6″-E-dicoumaroyl)glucopyranoside (140), and verbascoside (227) from the ethanolic extract
of B. lanata (China) [168]. Their anti-inflammatory activity was investigated in the same animal models employed for the plant extract. Compound 227 had a higher anti-inflammatory potential
than diclofenac (5 mg/kg b. w.), while the activity of compounds
139 and 140 were similar at 20–50 mg/kg b. w. doses. The butanol extract of this species furnished 2 other potentially anti-inflammatory compounds: the flavone C-glycosides panzeroside A
(156) and B (157) [173]. A paw edema reduction volume in rats
equal to that of 5 mg/kg b. w. of diclofenac was achieved with
30 mg/kg b. w. of both compounds.
Antibacterial activity
Because of the growing human health danger represented by the
antibiotics-resistant bacterial strains and in consideration of the
therapeutic uses of many species of Ballota and Otostegia genera
in microbial related pathologies, as well as in wounds and burns
treatments, the antimicrobial activity of EOs, plant parts extracts,
and also individual compounds has been extensively investigated.
Rosselli S et al. A Review of …
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▶ Table 14 reports a synopsis of the most relevant evidence in the
literature.
The MIC and MBC values may vary over a wide interval and are
often lower in order of magnitude than that of the antibiotics selected as positive controls. For example, the ethanolic extract of
B. acetabulosa was found to be significantly active against Escherichia coli with MIC and MBC values equal to ampicillin (32, and
64 µg/mL, respectively). On the contrary, the same extract was inactive against Pseudomonas aeruginosa (Schroeter) Migula (MIC
and MBC 1.02 mg/mL) [250].
The direct relation between the chemical composition of the
plant extracts and the antimicrobial activity is not always clearly
explainable. Sometimes this relation is evident as in the case of
the antimicrobial activity of B. pseudodictamnus EO from Greece
[220]. Its antibiotic activity was assessed against a panel of
6 pathogenic microorganisms, along with the activity of the principal components of the oil individuated by GC‑MS. Unsurprisingly, the MIC of the main component caryophillene oxide (from
0.07 to 5.20 µg/mL) was from 4 to 6 times stronger than that of
the whole oil, in which caryophillene oxide is present at 22.8 %!
The author stated, “The antibacterial property of the oil is suspected to be associated with the high percentage of caryophyllene oxide which is known to possess strong antibacterial activity.” The data reported seem to show any other component of this
EO as a mere diluent! This is just an example of how the rather
vague postulate of the “synergistic effect” of natural product mixtures in biological systems should at least be deeply questioned.
Another example of antibacterial activity of a caryophillene rich
EO is in the study of B. saxatilis subsp. brachyodonta from Turkey
[221]. A MIC of 50 µg/mL against all of the bacterial genera evaluated was found; caryophillene, caryophillene oxide, and epi-bicyclosesquiphellandrene were the main components of the oil.
An example of the lack of a molecular explanation is the study
of the activity of the water and methanolic extract of leaves of
B. africana from South Africa [251]: MICs were reported at 438
and 370 µg/mL versus Klebsiella pneumoniae (Schroeter) Trevisan
for methanolic and water extracts, respectively. However, an
attempt to isolate single bioactive compounds using bio-guided
fractionation of the crude extract failed. Additionally, the authors
underlined, for not so evident reasons, the apparent discrepancy
between the observed antibacterial activity and the lack of
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▶ Fig. 10 Structures of flavanones and flavanols.
Reviews
No
Name
Taxa
76
apigenin
B. acetabulosa [75, 134, 135]; B. deserti [89]; B. hirsuta [136, 137]; B. lanata [138];
B. nigra [139]; B. pilosa [140]
77
6-methylapigenin
O. persica [141, 142]
78
genkwanin
B. hirsuta [136]
79
apigenin 7,4′-dimethyl ether
B. inaequidens [73, 75, 76]; B. lanata [143–145]; B. pseudodictamnus [79]; B. rotundifolia [73]
80
ladanein
B. acetabulosa [73]; B. hirsuta [136]; B. inaequidens [75]; B. latibracteolata [73]; B. nigra [115];
B. rotundifolia [73]; B. saxatilis [73]; B. saxatilis ssp. brachyodonta [146]
81
salvigenin
B. glandulosissima [75, 147]; B. hirsuta [136]
82
scutellarein 7,4′-dimethyl ether
B. acetabulosa [75, 134]
83
cirsimaritin
B. andreuzziana [148]; B. pilosa [140]
84
pectolinarigenin
O. fruticosa [149]
85
luteolin
B. acetabulosa [135]; B. hirsuta [136]; B. lanata [138]; B. nigra [139]
86
luteolin 7-methyl ether
B. andreuzziana [148]
87
pilloin
B. cinerea [87]
88
luteolin-7,3′,4′-trimethyl ether
B. glandulosissima [73, 75, 147]; B. inaequidens [73, 75, 76]; B. lanata [145]
89
nuchensin
B. hirsuta [136]
90
velutin
B. glandulosissima [73, 75, 147]; B. undulata [150]
91
chrysoeriol
B. lanata [138]; B. nigra [139]; O. persica [141, 142]
92
5-hydroxy-3′,4′,6,7-tetramethoxy flavone
O. limbata [151]
93
eupatorin
O. limbata [151, 152]
94
3′,6-dihydroxy-4′,5,7-trimethoxy-flavone
O. persica [153]
95
4′,5,6,7-tetramethoxyflavone
B. cinerea [154]
96
tangeretin
B. nigra [155]
97
corymbosin
B. glandulosissima [73, 75, 147]
98
6,5′-dihydroxy diosmetin
O. fruticosa [156]
▶ Table 7 Distribution of flavonols in Ballota and Otostegia taxa.
No
99
Name
Taxa
kaempferol
B. deserti [157]; B. lanata [29, 138, 145]; O. persica [158]
100
quercetin
B. deserti [157]; B. lanata [29, 138, 143]; B. macrodonta [159]; O. persica [158, 160]
101
isorhamnetin
B. lanata [138, 145]
102
quercetin 3,7,3′,4′-tetramethyl ether
B. undulata [150]
103
5-hydroxy-3,7,4′-trimethoxyflavone
B. inaequidens [73, 76]; B. nigra ssp. foetida [73]; B. rotundifolia [73]; B. saxatilis [73, 75]
104
isokaempferide
B. hirsuta [136]
105
kaempferol 3,7,4′-trimethyl ether
B. saxatils ssp. brachyodonta [146]; B. undulata [150]
106
kumatakenin
B. glandulosissima [73, 75, 147]; B. hirsuta [136]; B. nigra ssp. anatolica [73]; B. nigra ssp.
foetida [73]
107
pachypodol
B. glandulosissima [73, 75, 147]; B. inaequidens [73, 75, 147]; B. undulata [150]
108
retusin
B. glandulosissima [147]; B. inaequidens [75, 76]; B. nigra ssp. foetida [73]; B. saxatilis [73];
B. saxatils ssp. brachyodonta [146]
109
5-hydroxy-3,6,7,4′-tetramethoxy flavone
B. inaequidens [73, 76]; B. saxatilis [73]
110
morin
O. persica [153, 160]
111
filindulatin
B. inaequidens [75]
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▶ Table 6 Distribution of flavones in Ballota and Otostegia taxa.
▶ Table 8 Distribution of flavonoid glycosides, flavanones, and flavanols in Ballota and Otostegia taxa.
No
Name
Taxa
apigenin-7-O-β-D-glucopyranoside
B. acetabulosa [161]; B. deserti [89, 157]; B. hirsuta [136, 137];
B. lanata [138, 144]; B. larendana [162]; B. nigra ssp. foetida [163];
B. pseudodictamnus [162]; B. undulata [164]; O. persica [141, 142]
113
apigenin-7-O-β-D-glucuronide
B. deserti [89]
114
apigenin-7-O-β- neohesperidoside
B. deserti [89, 90]
115
acacetin-7-O-β-D-glucopyranoside
B. acetabulosa [75, 134]
116
luteolin-7-O-β-D-glucopyranoside
B. andreuzziana [148]; B. hirsuta [136, 137]; B. lanata [29, 138];
B. larendana [162]; B. macrodonta [159]; B. undulata [150, 164]
117
luteolin-7-O-β-D-glucuronide
O. fruticosa [156]
118
luteolin-7-O-β-D-rutinoside
B. hirsuta [136]
119
diosmetin-7-O-β-D-glucopyranoside
B. undulata [150]
120
chrysoeriol-7-O-β-D-glucopyranoside
B. acetabulosa [75, 134, 161]; B. hirsuta [137]; B. pseudodictamnus [162];
O. fruticosa [149]
121
6,4′-di-O-methyl-scutellarein-7-O-β-glucopyranoside
B. andreuzziana [148]
Flavonol glycosides
122
quercetin-3-O-β-D-glucopyranoside (isoquercetin)
B. cinerea [88]; B. hirsuta [136]; B. lanata [138]
123
quercetin-3-O-β-galactopyranoside
B. lanata [144]
124
rutin
B. acetabulosa [135]; B. cinerea [88]; B. deserti [157]; B. lanata [29, 138,
143]; B. macrodonta [159]; B. undulata [164]
125
quercetin-3-O-α-L-rhamnopyranoside
B. lanata [29, 138]
126
quercetin-3-O-β-L-rhamnopyranoside
B. cinerea [165]
127
quercetin-7-O-β-L-rutinoside
B. andreuzziana [148]
128
isorhamnetin-3-O-β-D-glucopyranoside
B. lanata [138, 144, 145]; O. persica [166]
129
isorhamnetin-3-O-β-D-rutinoside
B. lanata [138, 144]
130
isorhamnetin-3-O-β-D-galactopyranoside
B. lanata [138]
131
isorhamnetin-7-O-β-D- rutinoside
B. lanata [145]
132
kaempferol-3-O-β-D-glucopyranoside
B. lanata [138, 143, 145]
133
kaempferol-3-O-β-D-rutinoside (nicotiflorin)
B. cinerea [88]; B. lanata [138]
134
kaempferol-7-O-β-D-glucopyranoside
B. lanata [138]
135
kaempferol-3-O-[β-D-glucopyranosyl-(1 → 2)-{β-D-glucopyranosyl(1 → 3)}-{β-D-glucopyranosyl-(1 → 4)}-α-L-rhamnopyranoside]-7-O[α-L-rhamnopyranoside]
O. limbata [167]
Acyl flavonoid glycosides
136
apigenin-7-(p-coumaroyl)-glucoside
B. hirsuta [136, 137]
137
apigenin-7-O-β-D-(3′′-p-E-coumaroyl)glucopyranoside
B. larendana [162]
138
apigenin-7-O-β-D-(4′′-E-p-coumaroyl)glucopyranoside (echinaticin)
B. acetabulosa [161]; O. persica [141, 142]
139
apigenin-7-O-β-D-(6′′-E-p-coumaroyl)glucopyranoside (terniflorin)
B. deserti [89]; B. lanata [138, 168, 169]; B. larendana [162]; B. pilosa [140]
140
apigenin-7-O-β-D-(2″,6″-E-dicoumaroyl)glucopyranoside
B. lanata [168]
B. hirsuta [137]
141
luteolin-7-(p-coumaroyl)glucopyranoside
142
luteolin-7-lactate
B. nigra [170]
143
luteolin-7-O-[2-O-β-D-glucopiranosyl-lactate]
B. nigra [170]
144
chrysoeriol-7-(p-coumaroyl)glucopyranoside
B. hirsuta [137]
145
chrysoeriol-7-O-β-D-(3′′-E-p-coumaroyl)-glucopyranoside
B. acetabulosa [161]; B. pseudodictamnus [162]
146
chrysoeriol-7-O-β-D-(3′′-Z-p-coumaroyl)glucopyranoside
B. acetabulosa [161]
B. lanata [138]; B. undulata [150]
147
chrysoeriol-7-O-β-D-(6′′-p-coumaroyl)glucopyranoside
148
kaempferol-7-O-β-D-(6′′-p-coumaroyl)glucopyranoside
B. lanata [138]
149
kaempferol-3-O-β-D-(6′′-p-coumaroyl)glucopyranoside
B. lanata [138]
continued
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Flavone glycosides
112
Reviews
No
Name
Taxa
150
5,6,7,4′-tetrahydroxyflavone-7-O-β-D(6′′-E-p-coumaroyl)glucopyranoside
B. lanata [144]
151
5,6,7,4′-tetrahydroxyflavone-7-O-β-D(6′′-E-caffeoyl)glucopyranoside
B. lanata [144]
152
leufolins B
B. arabica [171]
153
5-hydroxy-2-(4-hydroxyphenyl)-4-oxo-7-[(α-L-rhamnopyranosyl)oxy]4H-chromen-3-yl β-D-glucopyranosyl-(1 → 2)-[β-D-glucopyranosyl(1 → 4)]-[6-O-[(2E)-3-(4-hydroxyphenyl) prop-2-enoyl]-β-D-glucopyranosyl-(1 → 3)]-α-L-rhamnopyranoside
O. limbata [172]
154
5-hydroxy-2-(4-hydroxyphenyl)-4-oxo-7-[(α-L-rhamnopyranosyl)oxy]4H-chromen-3-yl [6-O-[(2E)-3-(4-hydroxyphenyl)prop-2-enoyl]-β-Dglucopyranosyl-(1 → 2)]-[β-D-glucopyranosyl-(1 → 4)]-[6-O-[(2E)-3(4-hydroxyphenyl)prop-2-enoyl]- β-D-glucopyranosyl-(1 → 3)]-α-Lrhamnopyranoside
O. limbata [172]
155
kaempferol-3-O-[β-D-glucopyranosyl-(1 → 4)-β-D‑6′′”’[4-hydroxy-(E)cinnamoyl]glucopyranosyl-(1 → 3)-{β-D-glucopyranosyl-(1 → 2)}-α-Lrhamnopyranoside]-7-O-[α-L-rhamnopyranoside]
O. limbata [167]
C-glycosyl flavonoids
156
panzeroside A
B. lanata [173]
157
panzeroside B
B. lanata [173]
158
isovitexin
O. persica [158]
159
vicenin-2
B. aucheri [174]; B. hirsuta [136]; B. nigra ssp. foetida [163];
O. fruticosa [156]; O. persica [166]
Flavanones, flavanone glycosides
160
naringenin
B. acetabulosa [135]
161
naringenin-7-O-β-D-glucopyranoside
B. macrodonta [159]
162
naringin
B. acetabulosa [135]
163
leufolins A
B. arabica [171]
Flavanols
164
epicatechin
B. acetabulosa [135]; B. macrodonta [159]
165
catechin
B. macrodonta [159]
166
epigallocatechin gallate
B. macrodonta [159]
resveratrol in the extract. Furthermore, in one case, the demonstration of the lack of antibacterial activity versus Propionicbacterium acnes (Gilchrist) Douglas of Italian B. nigra extract demonstrated the inconsistency of its claimed ethnopharmacological
use as an anti-acne remedy [262]. In some cases, the antimicrobial activity of a certain species may vary greatly depending on
the extraction solvent and the target investigated. A clear example is the case of the aerial part of Iranian O. persica [261]: the initial ethanolic extract was portioned in fractions soluble in n-Hex,
CHCl3, and finally MeOH. The lowest MIC and MBC values were
1.25 mg/mL for the CHCl3 ext. against Staphylococcus aureus and
Enterococcus faecalis, while the MeOH extc. had a 25 mg/mL MIC
for Listeria monocytogens (E. Murray et al.) Pirie. Finally, the bacteria species E. coli, P. aeruginosa, Salmonella spp., Klebsiella spp., and
Proteus spp. were completely insensitive to all of the extracts.
In other cases, the different geographical origin of the plant
material may be the cause of strong differences in the bioactivity,
as is the case of the EO derived from O. fruticosa. The plant har-
vested in Egypt is characterized by antibacterial activity with MIC
in the order of µg/mL [224]. On the contrary, the same taxa from
Yemen show MIC values 2 order of magnitude higher than the former [222]. This difference can be explained by the deep difference in the composition of the 2 oils, regarding their main components in particular, as discussed above.
▶ Table 14 includes cases where the crude extracts were further portioned with organic solvents in the attempt to concentrate the more active compounds [253, 254, 257], as well as other
cases, where the bioactivity was evaluated for single isolated molecules [76, 89, 187]. In most, highly polar extracts obtained with
protic solvents and water contained mainly phenols, phenylpropanoids, and glycosylates. Only 1 case reports the isolation and the
measurement of the antibacterial activity of terpenes from the Ac
extract of B. saxatilis subsp. saxatilis from Turkey [80].
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▶ Table 8 Continued
▶ Fig. 13 Structures of carotenoids and nitrogen containing compounds.
Antifungal activity
The general points discussed for antibacterial activity are valid
also in this case, as methodological approaches are obviously similar and a lot of investigations involve both bacterial and fungal
species as targets. ▶ Table 15 summarizes the most relevant data
reviewed.
Antitumor activity
▶ Fig. 12 Structures of carboxylic acids.
Rosselli S et al. A Review of …
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The EO of Ballota undulate, B. saxatilis, and B. nigra collected in Italy
were assessed for their in vitro cytotoxicity toward the Hep-G2
hepatocarcinoma and MCF-7 breast carcinoma cell lines [218].
The 3 oils showed moderate inhibition values against the former
target (IC50: 54.7, 65.4, and 69.9 µg/mL, respectively) and low values for latter (> 100 µM). Sesquiterpenes were found as major
components in the oils. The MCF-7 cells were instead more sensitive to the EO of O. fruticosa with an IC50 of 55.1 µg/mL. This taxon
was moderately active also against MDA‑MB‑231 cells with IC50 of
72.3 µg/mL [222].
Rhabdomyosarcoma cells were found to be sensitive to treatment with the methanolic extract of O. limbata from Pakistan
[266]. Cell viability tests showed up to 93 % mortality after 72 h,
a higher level than cisplatin (23 %).
The EtOH extract of AP of B. cinerea was assessed for its cytotoxicity against several cancer cell lines, showing moderate activity [267] with the following LC50 values (µg/mL): 131.8 for SK‑MEL
2, 275.4 for BE (2) C, and 302.0 for U87MG.
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▶ Fig. 11 Structures of triterpenes and steroids.
Reviews
▶ Table 9 Distribution of triterpenes, steroids, carboxylic acids, and carotenoids in Ballota and Otostegia taxa.
No
Names
Taxa
α-amyrin
O. fruticosa [175]
168
β-amyrin
B. cinerea [154, 176], O. persica [177]
169
betulin
B. cinerea [176],
170
betulonic acid
B. cinerea [154]
171
friedelin
B. aucheri [174], B. cinerea [154]
172
lupeol
O. fruticosa [175]
173
moronic acid
B. cinerea [178]
174
oleaonolic acid
B. nigra [179], B. cinerea [180] O. fruticosa [156]
175
oleanolic acid 3-acetate
B. pilosa [140]
176
ursolic acid
B. arabica [181], B. nigra [179], O. fruticosa [156]
Steroids
177
campesterol
O. persica [177]
178
3β-hydroxy-35-(cyclohexyl-5′-propan-7′-one)33-ethyl-34-methyl-bacteriohop-16-ene
B. cinerea [182]
179
leucisterol
B. arabica [181]
180
β-sitosterol
B. arabica [181], B. cinerea [87, 154, 176], B. deserti [24], B. lanata [29, 143], B. nigra [115, 183],
B. pilosa [140], O. fruticosa [156, 175], O. persica [177]
181
β-sitosterol 3-acetate
O. persica [177]
182
β-sitosterol-3-O-β-D-glucopiranoside
B. cinerea [154], B. deserti [24], B. lanata [29, 143], B. pilosa [140]
183
stigmasterol
B. aucheri [174], B. cinerea [87, 176, 182], B. deserti [24], B. lanata [143], B. pilosa [140],
B. undulata [81], O. integrifolia [100], O. persica [177]
stigmasterol-3-O-β-D-glucopiranoside
B. pilosa [140]
184
Carboxylic acids
185
caffeic acid
B. acetabulosa [135], B. arabica [184], B. lanata [29, 145], B. macrodonta [159], B. nigra [139, 185],
O. fruticosa [156], O. persica [177]
186
E-caffeoyl-L-malic acid
B. hirsuta [186], B. lanata [29], B. nigra [185–189], B. pseudodictamnus [162], B. rupestris [186]
187
4-O-caffeoylquinic acid
B. macrodonta [159]
188
chlorogenic acid
B. acetabulosa [135], B. lanata [29], B. macrodonta [159], B. nigra [139, 185]
189
E-cinnamic acid
B. deserti [157], O. persica [158]
190
E-coumaric acid
B. acetabulosa [135], B. hirsuta [137], B. macrodonta [159]
191
ellagic acid
B. macrodonta [159]
192
ferulic acid
B. arabica [184], B. macrodonta [159], B. nigra [139], O. fruticosa [149]
193
fumaric acid
B. nigra [185]
194
gallic acid
B. acetabulosa [135], B. arabica [184], B. cinerea [176], B. deserti [157], B. macrodonta [159]
B. macrodonta [159]
195
gentisic acid
196
4-hydroxy benzoic acid
B. arabica [181], B. deserti [157], B. macrodonta [159], O. persica [177]
197
jasmonic acid 5′-β-D-glucopyranosyloxy
B. cinerea [88]
198
laballenic acid
B. nigra [188]
199
neochlorogenic acid
B. lanata [29], B. macrodonta [159]
200
quinic acid
B. nigra [185]
201
rosmarinic acid
B. acetabulosa [135], B. macrodonta [159]
202
salicylic acid
B. macrodonta [159]
203
shikimic acid
B. nigra [185]
204
syringic acid
B. macrodonta [159]
205
tariric acid
B. cristata [190]
206
urticic acid
B. arabica [181]
207
vanillic acid
B. macrodonta [159]
continued
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Triterpenoids
167
▶ Table 9 Continued
No
Names
Taxa
carotene
B. lanata [29]
209
lutein
B. lanata [29]
210
neoxanthin
B. lanata [29]
211
violaxanthin
B. lanata [29]
212
zeaxanthin
B. lanata [29]
Precalyone (45) was isolated, together with other diterpenes,
from the ethanolic extract of the leaves and the stems of B. cinerea
[86]. This compound was active against the murine P-388 lymphocytic leukemia.
Docking studies of 18 phyto compounds from the plant B. nigra
of the family Lamiaceae were carried out. From the results, ballotinone (10), and ballonigrin (5) were found to have the best binding efficiency with the active site residues of the protein. The
binding energies of the 2 compounds were − 12.0691 kcal/mol
and − 10.2564 kcal/mol, respectively. This study provides a promising anti-cervical cancer inhibitor for further drug development
[268].
7α-Acetoxyroyleanone (73), also occurring in B. nigra [115],
was shown to be an active anticancer agent against both
MIAPaCa-2 and melanoma (MV-3) cancer cell lines (IC50 = 4.7 and
7.4 µg/mL, respectively) [269]. Additionally, it also exhibited cytotoxic activity against 5 more human cancer cell lines including,
breast (MCF-7), human leukemia (CEM and HL-60), murine skin
(B16), and colon cancer (HCT-8) cell lines in the range of
IC50 = 0.9–7.6 µg/mL. Its cytotoxic activity seemed to be related
to inhibition of DNA synthesis [270].
The anticancer activity of marrubenol (36), present in B. pseudodictamnus [79], against osteosarcoma cells along with evaluating its effects on autophagic cell death, reactive oxygen species
generation and cell migration and invasion tendency was evaluated. The results indicated that compound 36 exhibited an IC50
value of 45 µM and exerted its cytotoxic effects in a dose-dependent manner. Moreover, it was observed that the drug inhibited
colony formation and induced autophagy dose-dependent [271].
A moderate antiproliferative effect on lung adenocarcinoma
cell line (H1975 and XLA-07) and mouse mononuclear macrophage leukemia cell line (RAW264.7) was detected for leoheterin
(34) [272], a labdane diterpenoid occurring in B. aucheri [71, 74,
97] and O. fruticosa [82, 98].
Other bioactivities in vitro
The efficacy of B. nigra in its traditional neurosedative use was
proven by assessing the binding activity in dopaminergic, benzodiazepine, and morphinic receptors of a number of compounds
isolated from the leaf extract in EtOH/H2O 1 : 1 [236]: (+)-(E)-caffeoyl-L-malic acid (186), verbascoside (227), forsythoside B (223),
arenarioside (220), and ballotetroside (221). These molecules
were active with IC50 values ranging from 0.4 to 10 µM.
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▶ Fig. 14 Structures of other compounds.
The labdane diterpene cinereanoid D (16), the flavonoid glycosides isoquercetin (122), nicotiflorin (133), and martynoside
(226) isolated from the aerial part extract (95 % EtOH) of B. cinerea, collected in India [88], significantly inhibited the ATP binding
of a tumor growth-promoting heat shock protein, Hsp90. No significant binding inhibition was revealed for the protein Hsp70.
B. nigra [253] and B. pseudodictamnus [257] from Pakistan were
evaluated by the same group for their anti-leishmanial activity.
The extracts of the plant stems, leaves, and roots in EtOH were
partitioned between water and several organic solvents: n-Hex,
EtOAc, chloroform, and n-BuOH. The single subfractions of the
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Carotenoids
208
Reviews
▶ Table 10 Distribution of N-derivatives, phenylpropanoids, and other metabolites in Ballota and Otostegia taxa.
No
Names
Taxa
Nitrogen-containing compounds
213
choline
B. nigra subsp. foetida [191]
214
cinerealactam E
B. cinerea [88, 182]
215
4-hydroxyprolinebetaine
B. nigra [188], B. undulata [150]
216
1-methylindole-3-carboxaldehyde
B. cinerea [87]
217
stachydrine
B. lanata [138, 192], B. nigra [188], B. nigra subsp. foetida [191], B. undulata [150]
alyssonoside
B. nigra [185, 187]
219
angoroside A
B. nigra [187]
220
arenarioside
B. nigra [94, 187, 193]
221
ballotetroside
B. nigra [94, 185, 187, 194]
222
betonyoside F
B. undulata [150]
223
forsythoside B
B. deserti [89, 90], B. hirsuta [186], B. nigra [94, 115, 185–189, 193],
B. pseudodictamnus [162], B. rupestris [186], B. undulata [150]
224
lavandulifolioside
B. nigra [187]
225
lysionotoside
B. undulata [150]
226
martynoside
B. cinerea [88], B. nigra [115]
227
verbascoside (acteoside)
B. deserti [89, 90], B. hirsuta [186], B. lanata [29, 144, 168], B. nigra [94, 185–189, 193,
195], B. pseudodictamnus [162], B. rupestris [186], B. undulata [150]
Other metabolites
228
8-O-acetylharpagide
O. fruticosa [82]
229
anthroquinone1,4-dihydroxy-6,7-dimethoxy
2-methyl 3-O-β-D-glucopyranoside
B. cinerea [165]
230
eutigoside A
B. acetabulosa [161]
231
4-hydroxybenzaldehyde
B. macrodonta [159]
232
4-methoxybenzyl benzoate
B. arabica [184]
233
4-methyl-catechol
B. deserti [157]
234
7-methoxy coumarin
B. lanata [145]
235
oleuropein
B. acetabulosa [135]
236
phytol
B. deserti [24], B. nigra [183], B. nigra subsp. anatolica [196]
237
stachyose
B. nigra subsp. foetida [197]
238
undatuside A
B. cinerea [88]
239
verminoside
B. undulata [150]
2 species showed the ability to inhibit the parasite development
process at various stages.
The leaves of B. deserti harvested in Tunisia were extracted in a
solvent of increasing polarity [25]. MeOH, BuOH, and EtOAc extracts showed significant antiviral activity against coxsakie B3
virus with IC50 values ranging from 100 to 135 µg/mL and with a
selective index above 3.
The genotoxic and antigenotoxic activities of some B. deserti AP
extracts in various solvents were evaluated on E. coli PQ37 cells by
the SOS Chromotest. Additionally, a number of pure compounds
isolated from the same plant were included in this investigation
[89]. EtOAc, MeOH, and BuOH extracts proved moderately to
highly genotoxic in a dose-dependent manner, while apigenin-7O-β-neohesperidoside (114), verbascoside (227), apigenin-7-Oβ-D-glucopyranoside (112), and apigenin (76) resulted as margin-
ally genotoxic. Furthermore, the protective effect of all extracts
and the isolated compounds was studied on nitrofurantoin (NF)
induced damage. MeOH, EtOAc, and BuOH extracts significantly
decreased the induction factor of NF by 89.8 %, 94.3 %, and
96.2 %, respectively, while compounds 76, 112–114, 139, 223,
and 227 decreased the genotoxicity by a factor of 65 to 97 %.
Insecticidal activity
The hot water extract of the leaves of B. undulata from Jordan
[273] was effective as a repellent agent against the sweet potato
parasite Bemisia tabaci (Gennadius). A set of tomato leaves treated
with the extract was compared with untreated tomato leaves,
demonstrating a significant difference (analysis of variance test)
in the number of insects that attacked each group. The same taxon, in the form of leaves brewed in hot water, showed acaricidal
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Penylpropanoids
218
▶ Table 11 Occurrence of non-volatile metabolites in taxa of Ballota and Otostegia.
Taxa
Diterpenes
Flavonoids
Others
B. acetabulosa
5, 18, 25, 33
76, 80, 82, 85, 112, 115, 120, 124, 138,
145, 146, 160, 162, 164
185, 188, 190, 194, 201, 230, 235
B. africana
25
B. andreuzziana
25
B. antalyensis
5, 18
B. arabica
75
152, 163
176, 179, 180, 182, 185, 192, 194, 196, 206, 232
B. aucheri
4, 5, 10, 27, 28, 29,
30, 31, 34, 44, 46
159
185, 188, 190, 194, 201, 230, 235
B. cinerea
12, 13, 14, 15, 16,
45, 74
87, 95, 122, 124, 126, 133
168–171, 173, 174, 178, 180, 182, 183, 194,
197, 214, 216, 226, 229, 238; cetyl alcohol, glucose, fructose, arabinose, palmitic acid, stearic
acid, oleic acid, oxalic acid, tartaric acid [176];
hentriacontane, triacontane [116]; pentacosane,
octacosanol [154]
B. cristata
5, 18, 25
B. deserti
2, 3, 19, 17, 20, 21,
24, 37–40
204; linoleic acid, oleic acid, palmitic acid,
stearic acid, linolenic acid [190]
76, 99, 100, 112–114, 124, 139
180, 182, 183, 189, 194, 196, 223, 227, 233, 236
81, 88, 90, 97, 106, 107, 108
B. hirsuta
25
B. hispanica
51, 52
B. inaequidens
5, 25
79, 80, 88, 103, 107–109, 111
B. lanata
5, 32
76, 79, 85, 88, 91, 99, 100, 101, 112,
116, 122–125, 128–132, 134, 139, 140,
147–151, 156, 157
B. larendana
5, 18
112, 116, 137, 139
B. latibracteolata
18
80
B macrodonta
18
100, 116, 124, 161, 164–166
185, 187, 188, 190–192, 194–196, 199, 201,
202, 204, 207, 231
B. nigra
1, 5, 32,73
76, 80, 85, 91, 96, 142, 143
174, 176, 180, 182, 185, 186, 188, 192, 193,
198, 200, 203, 215, 217–221, 223, 224, 226,
227, 236; oxalic acid, aconitic acid, citric acid,
ascorbic acid, malic acid [185]; linoleic acid
α-linolenic acid, oleic acid, palmitic acid, stearic
acid [198]
106
236; 10-undecenoic acid, myristic acid, palmitoleic acid, palmitic acid, 11,13-dimethyl-12-tetradecen-1-ol acetate, linoleic acid, oleic acid, linolenic acid, stearic acid, arachidic acid, 7-methyl-6hexadecenoic acid, behenic acid [196]
103, 106, 108, 112, 159
213, 217, 237; palmitic acid, stearic acid,
octadecenoic acid, octadecadienoic acid,
octadecatrienoic acid [199]
76, 139
175, 180, 182–184
79, 112, 120, 145
186, 223, 227
B. nigra subsp. anatolica
B. nigra subsp. foetida
5, 9, 10, 37, 47
B. nigra f. uncinata.
18
B. pilosa
B. pseudodictamnus
5, 33, 36
B. pseudodictamnus subsp. lycia
18, 25
B. rotundifolia
18, 25
B. rupestris
5, 8, 49
76, 78, 80, 81, 85, 89, 104, 106, 112,
116, 118, 120, 122, 136, 141, 144, 159
186, 190, 223, 227
176, 180, 182, 183, 185, 186, 188, 199,
208–212, 217, 227, 234
79, 80, 103
186, 223, 227
B. saxatilis
5, 18, 25, 33
80, 103, 108, 109
B. saxatilis subsp. brachyodonta
5, 18
80, 105, 108
continued
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B. glandulosissima
83, 86, 116, 121, 127
Reviews
▶ Table 11 Continued
Taxa
Diterpenes
Flavonoids
Others
B. undulata
5, 8, 10, 26
90, 102, 105, 107, 112, 116, 119, 124,
147
183, 215, 217, 222, 223, 225, 227, 239;
(−)-carvone, [81]
O. fruticosa
5, 22, 23, 34, 35,
41, 42, 46, 50
84, 98, 117, 120, 159
167, 174, 176, 180, 185, 192; octacosane,
palmitic acid, linoleic acid, arachidic acid [175]
O. integrifolia
43, 48
O. limbata
6, 7, 53–72
92, 93, 135, 153–155
O. persica
56, 59, 71, 72
77, 91, 94, 99, 100, 110, 112, 128, 158,
159
183; pentatriacontane [100]
activity against the spider mite Tetranychus urticae. A high mortality (53 %) was achieved by treating adults with the extract, while
the eggs remained unaffected [274].
An insect repellent activity was also disclosed for O. integrifolia
from Ethiopia [275]. The headspace of fresh leaves, dried leaves,
and burned dried leaves were evaluated giving a repellent ratio
of 29–56 % in an elegant experimental setting developed by the
author. This activity was shown to be associated with the presence
of β-ocimene in the headspace blend.
The n-Hex extract of O. limbata (Pakistan) showed larvicidal activity against the banana parasite Drosophila melanogaster Meigen
[276]. The crude solid extract was mixed with overripe banana at
2–6 % w/w and larvae were let to feed. A concentration dependent
mortality from 12 to 89 % was observed. Also, a pupation reduction effect was established with a ratio of development dropping
from 88 to 23 %, depending on the extract concentration (0.5–
2.0 %).
The Ac extract of O. persica leaves collected in Iran [277] was
studied as a pesticide against Aphis fabae Scopoli, Aphis gossypii
Glov., Myzus persicae Sulzer, and Tribolium castaneum Herbst. The
maximum mortalities of individuals after 48 h of treatment at
80 µL/mL dose of extract were 55, 58, 88, and 34 %, respectively.
The prolongation of exposure time to 60 h did not appear to significantly improve the mortality rate.
An Ac extract of B. hirsuta (AP) from Spain [278] caused a significant growth inhibition in the T. castaneum larvae (29 %) accompanied by 20 % mortality. This effect was related to the harvesting
time, as the plant taken in November was active, while a sample
collected in April was inactive.
Two extracts of O. persica harvested in Iran were prepared by
suspending the AP of the plant in n-Hex and 80 % EtOH and were
tested for the alleviating effect in the opioid withdrawal syndrome
[281], as this is a traditional use in Iran folk medicine. Male mice
were intoxicated with morphine and the withdrawal signs (jumping, rearing, diarrhea, piloerection, tremor, and ptosis) were recorded after injection of naloxone in untreated animals, treated
with clonidine (0.2 mg/kg b. w.) and with increasing doses of both
the extracts (500–1500 mg/kg b. w.). All of the clinical signs were
reduced significantly to levels comparable to those obtained with
clonidine at the maximum dose of utilized ethanolic extract. The
n-Hex extract, however, was only able to reduce diarrhea.
An anticonvulsant effect was evidenced in the MeOH extract of
O. persica [282], sustaining the traditional use of this plant in seizure management with scientific evidence. Convulsions were induced in mice with pentylenetetrazole, followed by an IP injection
of 800 mg/kg b. w. which had a 93 % protective effect, comparable
to that of benzodiazepine.
The extract of AP of B. glandulosissima in water were investigated for their antinociceptive activity in mice by acetic acid-induced “writhing” and “tail-flick” tests [283]. A lethal dose of
8.85 g/kg b. w. was determined. The extract, intraperitoneally administrated at 100 and 200 mg/kg b. w. doses, had promising
antinociceptive activity, comparable to acetylsalicylic acid, utilized as a positive control.
An analgesic effect similar to paracetamol was obtained with
the MeOH extract of B. deserti AP from Algeria [248] when administrated at 400 mg/kg b. w. to albino rats. Acetic acid induced abdominal writhes were reduced by 73 %.
Effects on central nervous system
Metabolism control effects
The extract of B. limbata (Pakistan) leaves in n-buthanol was active
as antitussive by reducing the SO2-induced cough in mice. The
treatment of animals with 800 mg/kg b. w. of the extract caused
the cough episodes to be reduced from 46 to 12 in 60 min; an efficacy analogous to that of the standard antitussive drugs codeine
and dextromethorphan [279]. The toxicity test proved the extract
to be inoffensive until the dose of 5000 mg/g b. w.
The brew (in hot water) of the AP of B. nigra subsp. anatolica
from Turkey possess both antidepressant and anxiolytic activities
in rats, determined with the forced swimming and the elevated
plus-maze tests [280].
The extract of B. nigra from Jordan, obtained by brewing the AP in
EtOH water 7 : 3, was proven to possess very interesting hypoglycemic activity both in healthy and in allossana-induced diabetic albino rats. After a single dose treatment of 400 mg/g b. w., the first
group had a glucose blood concentration reduction from 96 to
62 mg/dL after 6 h, while for the second group, the value dropped
from 324 to 271 mg/dL [284]. In another study by the same authors [285], an analogous B. nigra preparation administrated at
the same dose for 7 d was also effective in reducing hematic cholesterol (from 193 to 144 mg/dL), triglycerides (from 97 to 83 mg/
dL), and CK protein (from 431 to 348 IU/L).
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168, 177, 180, 181, 183, 185, 189, 196; gerianol,
eugenol, ceryl alcohol, hentiacontane [177]
Taxa
Origin
Main compounds
Ref.
B. andreuzziana
F
G. Akhdar, Libya
caryophyllene (63.1), cis-γ-bisabolene (26.3), selinene (5.0)
[200]
B. aucheri
AP
Fars, Iran
α-cadinol (21.0), dehydroaromadendrene (11.8), β-caryophyllene (8.1), carvone (6.4),
spathulenol (6.0), linalool (4.8), (Z)-methyl isoeugenol (4.1), α-santalene (3.5)
[201]
B. deserti
AP
Djelfa, Algeria
germacrene D (45.7), β-bourbonene(4.0), α-terpinolene (3.9), δ-cadinene (3.8),
1-octen-3-ol (3.7), α-copaene (3.5)
[202]
AP
Ghardaïa, Algeria
9-methyl-undecene (21.3), δ-cadinene (12.2), germacrene D (11.9), cis-phytol (7.7),
α-cubebene (4.4)
[203]
AP
Algerian Sahara
tetracosane (31.1), germacrene D (7.9), δ-cadinene (6.5), α-cadinol (6.3) t-cadinol (5.8),
β-elemene (3.8)
[204]
B. hispanica
AP
Sicily, Italy
α-elemol (10.9), α-ylangene (8.5), γ-dodecalactone (5.1), manoyl oxide (4.8), γ-eudesmol
(4.2), β-eudesmol (3.7), 1-pentadecene (3.7), germacrene D (3.5),
[205]
B. lanata
AP
Buryatia, Russia
palmitic acid (14.3), camphor (12.4), α-pinene (10.3), linalool (9.1), β-caryophyllene (8.3),
terpinen-4-ol (6.4), phytol (4.8), caryophyllene oxide (4.2), p-mentha-3-en-8-ol (3.3)
[29]
AP
Gobi, Mongolia
camphor (14.4), α-pinene, (11.3), terpinenol-4 (5.3), 6,10,14-trimethyl-2-pentadecanone
(4.7), β-caryophyllene (3.5), β-humulene (3.2), α-thujene (3.1)
[206]
B. macedonica
B. nigra
B. nigra L. subsp.
anatolica
AP
Debar, Macedonia
germacrene D (24.6), (E)-caryophyllene (16.5), carotol (13.7), caryophyllene oxide (3.5)
[207]
AP
Prizren, Serbia
carotol (52.1), germacrene D (8.6), (Z)-hex-3-en-1-ol (7.0), (E)-caryophyllene (6.5)
oct-1-en-3-ol (3.8)
[207]
AP
Mazandaran, Iran
caryophyllene oxide (7.9), epi-α-muurolol (6.6), δ-cadinene (6.5), α-cadinol (6.3),
γ-amorphene (4.3), β-bourbonene (4.1), 6,10,14-trimethyl-2-pentadecanone (4.0),
(E)-caryophyllene (4.0), germacrene D (3.8), aromadendrene (3.4), γ-muurolene (3.2),
germacrene D-4-ol (3.2), α-bisabolol (3.2), α-amorphene (3.0)
[208]
S
Jadovnik Mt., Serbia
β-caryophyllene (35.4), germacrene D (27.4), α-humulene (7.4), δ-cadinene (3.8),
(E)-phytol (2.5)
[209]
L
Jadovnik Mt., Serbia
β-caryophyllene (39.1), germacrene D (35.7), α-humulene (10.4), (E)-phytol (3.8)
[209]
R
Jadovnik Mt., Serbia
p-vinylguiacol (9.2), borneol (7.5), myrtenol (7.1), trans-pinocarveol (5.2),
1-octen-3-ol (5.1), pinocarvone (4.4), 2-methyl-3-phenylpropanal (4.3),
p-cymen-8-ol (4.3), trans-carveol (3.5)
[209]
AP
Golestan, Iran
β-pinene (39.0), α-pinene (34.5), sabinene (7.7), α-phellandrene (4.1)
[210]
corollas
Kharkov, Ukraine
palmitic acid (573)a, 2,2,6-trimethyl-4-methylene-2H-pyran (172)a, hexahydrofarnesylacetone (167)a, miristic acid (100)a, caryophyllene oxide (57)a, pentadecanoic acid (50)a,
palmitoliec acid (40)a, germacrene D (40)a amg/kg
[211]
calyx
Kharkov, Ukraine
[211]
palmitic acid (1620)a, dodecanal (519)a, palmitoliec acid (306)a, miristic acid (271)a,
pentadecanoic acid (182)a, lauric acid (67)a, trans-isoelemicin (67)a, hexahydrofarnesylacetone (60)a, pentadecene (54)a, methyleugenol (40)a amg/kg
L
Kharkov, Ukraine
palmitic acid (656)a, palmitoliec acid (197)a, miristic acid (187)a, pentadecanoic acid (121)a, [211]
farnesylacetone (69)a, dihydroactinidiolide (44)a amg/kg
S
Kharkov, Ukraine
methylsalicilate (313)a, palmitic acid (130)a, 2,2,6-trimethyl-4-methylene-2H-pyran (42)a,
miristic acid (42)a amg/kg
[211]
AP
Mazandaran, Iran
germacrene D (18.1), nerolidol epoxyacetate (15.4), sclareol oxide (12.1), linalyl acetate
(11.5), β-caryophyllene (10.5), spathulenol (9.0), linalool (5.2), longipinene epoxide (4.7)
[212]
F
Çamlica, Turkey
hexenal (21.2), (E)-β-caryophyllene (10.0), germacrene D (7.8), cis-3-hexene-1-ol (6.8),
pentanal (6.9), limonene (5.2), (E)-2-hexenal (3.0)
[213]
AP
Muğla, Turkey
hexadecanoic acid (40.9), β-bisabolene (13.4), hexahydrofarnesyl acetone (7.9),
1-isobutyl-4-isopropyl-2,2-diemethyl succinate (6.6), β-eudesmol (3.5)
[214]
AP
Western Turkey
1-hexacosanol (26.7), caryophyllene oxide (9.3), germacrene-D (9.3), α-selinene (8.7),
Z-8-octadecen-1-ol acetate (7.1), 2,5-di-tertoctyl-p-benzoquinone (7.3),
arachidic acid (6.0), tetracosane (4.5), heneicosane (4.4), heptacosane (4.3),
2-methyl-1-hexadecanol (3.3), octadecane (3.0), butyl phthalate (3.0)
[196]
cont.
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▶ Table 12 Main compounds (> 3 %) of the essential oils from Ballota and Otostegia taxa.
Reviews
Taxa
Origin
Main compounds
Ref.
AP
Pisa, Italy
β-caryophyllene (25.1), germacrene D (24.2), 1-octen-3-ol (7.3), (E)-2-hexenal (6.1),
α-humulene (4.3), caryophyllene oxide (4.2)
[215]
AP
Urbino, Italy
β-caryophyllene (20.0), germacrene D (18.0), caryophyllene oxide (15.0),
1-octen-3-ol (6.8), (E)-2-hexenal (6.1), α-humulene (4.5), β-bourbonene (3.2)
[216]
AP
flowering
Urbino, Italy
β-caryophyllene (22.6), caryophyllene oxide (18.0), germacrene D (16.5),
(E)-2-hexenal (6.5), 1-octen-3-ol (5.5)
[217]
AP
fruiting
Urbino, Italy
β-caryophyllene (21.8), caryophyllene oxide (20.5), germacrene D (13.1),
(E)-2-hexenal (11.2), β-pinene (4.4), limonene (4.1), 1-octen-3-ol (3.5), linalool (3.5)
[217]
AP
Nis, Serbia
(E)-phytol (56.9), germacrene D (10.0), β-caryophyllene (4.7), caryophyllene oxide (3.6),
(E)-β-ionone (3.4)
[207]
AP
Brac, Croatia
germacrene D (23.1), β-caryophyllene (20.3), caryophyllene oxide (6.2), caryophylladienol I [218]
(3.3), (E)-2-hexenal (3.1), hexadecanoic acid (3.1), α-humulene (3.0)
AP
Kurdistan, Iran
caryophyllene oxide (39.4), β-caryophyllene (24.9), germacrene D (7.6), 1-undecene (4.2),
isoaromadendrene epoxide (3.2)
[219]
B. nigra f. uncinata AP
Konya, Turkey
caryophyllene oxide (21.2), hexadecanoic acid (19.9), β-caryophyllene (18.9), germacrene
D (4.6), hexahydrofarnesyl acetone (4.4), spathulenol (4.2), caryolphyllenol II (3.8);
bicyclogermacrene (3.7)
[214]
B. pseudodictamnus
AP
Crete, Greece
caryophyllene oxide (22.4), phytol (11.9), γ-muurolene (11.4), (E)-caryophyllene (10.7),
α-copaene (6.1), β-cucubene (5.3), hexahydrofarnesyl acetone (3.5)
[220]
B. saxatilis
AP
Amman, Jordan
linalool (14.6), caryophyllene oxide (11.0), acorenone (9.3), β-caryophyllene (7.9),
germacrene D (7.6), 1-octen-3-ol (3.6), β-bourbonene (3.0)
[215]
AP
Kfardin, Lebanon
linalool (11.2), (E)-β-caryophyllene (8.8), caryophyllene oxide (6.3), (E)-2-hexenal (5.6),
hexadecanoic acid (4.9), (Z,Z)-9,12-octadecadienoic acid (3.4)
[218]
B. saxatilis subsp.
brachyodonta
AP
Mersin, Turkey
(E)-β-caryophyllene (23.9), epi-bicyclosesqui-phellandrene (20.2), caryophyllene oxide
(10.5), γ-elemene (5.5), thymol (4.1)
[221]
Ballota schimperi
L
Yemen
τ-cadinol (9.3), β-caryophyllene (8.8), bornyl formate (5.2), myrtenyl formate (3.8),
spathulenol (3.2), β-selinene (3.0)
[222]
Turkey
linalool (5) (ratio (+)-linalool: (−)-linalool = 27 : 73)
[223]
AP
Naur, Jordan
germacrene D (19.1), bicyclogermacrene (11.6), viridiflorol (6.0), 1-octen-3-ol (3.5),
epi-10-γ–eudesmol (3.1)
[215]
AP
Kfardin, Lebanon
germacrene D (16.0), bicyclogermacrene (10.4), 9,12-octadecadienoic acid (5.3),
hexadecanoic acid (4.5), dihydroactinidiolide (3.4)
[218]
AP cultivated
El-Mansoura, Egypt
thymol (43.7), γ-terpinene (16.4), p-cymene (12.4), (E)-β-caryophyllene (9.5)
[224]
AP
Sinai, Egypt
caryophyllene oxide (60.8), β-bisabolene (9.2), 4-decyne (5.1), α-cis-bergamotene (4.4),
β-bourbonene (4.2), linalyl acetate (4.2)
[175]
O. integrifolia
Ls
North Shoa, Ethiopia
α-pinene (31.3), 1-octen-3-ol (11.8), β-caryophyllene (11.3), linalool (6.6), cis-β-ocimene
(5.9), germacrene D (3.3)
[56]
O. michauxii
AP
Zagros, Iran
caryophyllene oxide (20.1), trans-verbenol (10.2), linalool (5.3) and humulene epoxide II
(4.6)
[225]
AP
Fars, Iran
dillapiole (23.9), 2-methylbenzofuran (12.9), α-pinene (8.1), δ-cadinene (6.1),
1-octen-3-ol (4.9), caryophyllene oxide (4.8), linalool (4.5), (E)-β-caryophyllene (3.6)
[226]
AP
Fars, Iran
dillapiole (43.1), trans-verbenol (9.6), hexadecanoic acid (5.7), isospathulenol (4.5)
[227]
L
Sistan, Iran
[228]
hexahydrofarnesyl acetone (14.3), trans-verbenol (10.2), geranyl acetone (6.5),
pentadecane (5.9), hexadecane (5.9), α-pinene (4.5), trans-anethole (4.5), verbenone (3.5),
1-octen-3-ol (3.0)
F
Sistan, Iran
α-pinene (13.6), trans-verbenol (9.2), linalool (6.8), hexadecane (5.5), caryophyllene oxide
(4.8), pentadecane (4.6), trans-carveol (4.0), 1-octen-3-ol (3.8), geranyl acetone (3.7),
heptadecane (3.3)
[228]
flowering
AP
Kerman. Iran
hexadecanoic acid (31.7), pentacosane (29.5), α-copaene-8-ol (5.9), hexadecanoic acid
methylester (4.8), caryophyllene oxide (3.8), trans-damascenone (3.7)
[228]
F
Kerman. Iran
α-pinene (17.2), 1-octen-3ol (13.4), cubenol (7.3)
[229]
fruits
Kerman. Iran
diisooctyl phthalate (45.0), hexadecanoic acid (11.1)
[229]
B. nigra subsp.
foetida
B. nigra subsp.
kurdica
B. sechmenii
B. undulata
O. fruticosa
O. persica
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▶ Table 12 Continued
▶ Table 13 The antioxidant activity of Ballota and Otostegia taxa.
Origin
Sample preparation
(plant part-solvent)
Test
Ref.
Turkey
B. acetabulosa, B. antalyanse, B. cristata,
B. glandulosissima, B. inaequidens,
B. larendana, B. latibracteolata, B. macrodonta, B. nigra ssp. anatolica, B. nigra ssp.
foetida, B. nigra, B. nigra ssp. uncinata,
B. pseudodictamnus ssp. lycia, B. rotundifolia, B. saxatilis ssp. brachyodonta,
B. saxatilis
L: EtOAc, MeOH, W
FRAP (% inhib.): B. antalyense (1.34) MeOH extr., B. saxa- [230]
tilis ssp. brachyodonta MeOH extr. (1.28) B. saxatilis MeOH
extr. (1.12); B. antalyense W extr. (1.24)
B. antalyense, B. macrodonta, B. glandulo- Turkey
sissima, B. larendana, B. pseudodictamnus, B. nigra ssp. anatolica, B. rotundifolia,
B. saxatilis ssp. brachyodonta, B. saxatilis
L: EtOH/W 3 : 1
Superoxide anion formation quenching (SAFQ):
IC50 0.50 to 0.87 mg/mL; Liver rats lipid peroxidation
(LO): not significant
[231]
B. antalyense, B. macrodonta,
B. glandulosissima
Turkey
L: EtOH/W 3 : 1
SAFQ: 0.50, 0.51, 0.51
[231]
B. inaequidens, B. glandulosissima,
B. saxatilis, B. macrodonta, B. antalyense
Turkey
L: EtOH/W 3 : 1
LO (mg/mL): 12 to 20 mg/mL
[231]
B. inaequidens, B. glandulosissima
Turkey
L: EtOH/W 3 : 1
LO: (mg/mL) 12 and 15
[231]
B. aucheri
Pakistan
AP: 70 % MeOH
DPPH: IC50 (µg/mL) 2.23
B. cinerea
India
AP: EtOH, then partition in CHCl3, DPPH: IC50 (µg/mL) 85–661; FRAP (mmolFe/g) 0.14–
EtOAc, n-BuOH, W
0.59; ABTS IC50 (µg/mL) 60–840; ORAC (TEAC mM)
8.55–36.0
[233]
B. deserti
Tunisia
L: MeOH, then partition in pet.
ether, CHCl3, EtOAc, BuOH
DPPH: IC50 (mg/mL) 0.85–2.50; ABTS: IC50 (mg/mL)
0.35–13, pet. Ether inactive
[25]
B. deserti
Algeria
EO
DPPH: IC50 µg/mL 35.9
[204]
B. deserti
Algeria
AP: CH2Cl2, MeOH, then isolat.
compds: 114, 223, 227
ABTS: IC50 (g/mmol) 0.14–3.50
[90]
B. deserti
Algeria
AP: CH2Cl2, MeOH, then isolat.
compds: 76, 112–114, 139, 223,
227
ABTS: EC50 (mol %) 0.09-> 0.50; CUPRAC: E‰ (L/mol/cm) [89]
0.01–0.80; DPPH: EC50 (mol %) 0.39 – > 1.5, 9 and
12 oxidant or pro-oxidant
B. hirsuta
Algeria
L: W/MeOH 1 : 1, then partition in
EtOAc, CHCl3, n-BuOH
DPPH IC50 (mg/mL): 0.35 extr., 0.07 EtOAc, 0.26 CHCl3,
0.12 n-BuOH
B. nigra
ex vitro
Shoots: MeOH
DPPH EC50 (mg/mL): 56.0–202.6, FRAP (µmol/g) 331.5– [235]
642.4; LPO (% inhb.) 20.97–36.05
B. nigra
Czech
Republic
L: W
DPPH IC25 (µg/mL) 4.81; X/XO (µg/mL) 14.6; HClO scav.
80 % at 500 µg/mL; NO scav. IC25 (µg/mL) 122
B. nigra
France
[236]
L: 50 % EtOH, then isolat. compds: O22- scav: IC50 (µg/mL) 30.6–149.0; H2O2 scav.:
IC50 (µg/mL) 2.3–11.2; HClO scav.: IC50 (µg/mL) 1.5–9.3;
186, 220, 221, 223, 227
OH rad. scav.: IC50 (µg/mL) 26.7–64.7.
LDL‑Ox: ED50 (µM) 1.0–9.5
[237]
B. nigra ssp. anatolica
Turkey
WP: PE, Ac, MeOH, W
ABTS (% inhib. at 100 mg/mL): 72–80
[196]
B. rotundifolia
Turkey
AP: MeOH
DPPH (µg/mg) 138.0; LPO (% inhib.): 35.97
[238]
B. undulata
Jordan
L: MeOH: compds: 116, 119, 147, ABTS, TEAC (mM) 0.68–1.67
222, 223, 225, 227, 239
[150]
[232]
[234]
[185]
B. pseudodictamnus, B. acetabulosa
Grecia
L: MeOH
Activity equal to α-tocopherol in Umezawa essay
[239]
O. integrifolia
Ethiopia
L: EtOAc, MeOH
DPPH: 82.9 MeOH, 32.7 EtOAc;
[240]
O. integrifolia
Ethiopia
EO
DPPH: EC50 (µL/mL) 5.32
[56]
O. limbata
Pakistan
WP: MeOH
DPPH: IC50 (mg/mL) 13.53–129.52; FRAP, (mM/mL)
88.86–334.27; LPO: ([% inhib.] 12.67–61.76).
[241]
O. limbata
Pakistan
AP: MeOH then solubilization
in n-Hex, CHCl3, EtOAc, BuOH,
MeOH, W
DPPH: EC50 (µg/mL) 60–350; FRAP (mmol/mg) 5–41;
ABTS, TEAC (µmol/g) 30–139
[242]
cont.
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Species
Reviews
Species
Origin
Sample preparation
(plant part-solvent)
Test
Ref.
O. persica
Iran
WP: MeOH, then solubilization in
n-Hex and CHCl3
LPO (% inhib.) 95.87 MeOH, 2.5 nHex., 1.9 CHCl3
[158]
O. persica
Iran
EO
DPPH: IC50 (mM) 9.76
[228]
O. persica
Iran
EO in flowering
EO in fruiting
DPPH: IC50 (µg/mL) 19.8, 29.2; LPO (% inhib.) 93.8, 63.0
[229]
O. persica
Iran
AP: MeOH
LPO (% inhib.) 95.87
[160]
O. persica
Iran
AP: MeOH, EtOAc
DPPH: IC50 0.49 mg/mL for both
[141]
O. persica
Iran
L: 70 % EtOH, then partition in PE,
EtOAc, CHCl3, n-BuOH, MeOH
DPPH: IC50 (µg/mL) 170 (EtOH) to 1580 (pet. Et.)
[243]
Similar hypolipidemic effects were observed in rabbits treated
with the AP extract, in EtOH/water 7 : 3, of B. undulata from Jordan
[286]. Two animal groups were treated with 400 mg of cholesterol/kg b. w. per day dissolved in 5 mL of coconut oil for 120 d; in
1 group 1.2 g/kg b. w. per day of the extract were added to the
diet. A strong difference in lipidemic parameters was observed
for the 2 groups: total cholesterol 807 versus 104, HDL 246 versus
40, phospholipids 252 versus 112, triglycerides 259 versus 74. Despite their scientific relevance, in our opinion, the eventual transfer of these findings on human trials might be strongly inhibited
by the evident difficulty to orally administer a dose of 84 g/day of
plant extract to an average weight human.
A potent antidiabetic effect was identified for the ethanolic extract of the O. persica AP from Iran [287]. The hematic glucose level
of STZ-induced diabetic rats was normalized when animals received 200 to 500 mg/kg b. w. per day of the extract. At the maximum dose, the glucose level was lowered from 405–420 to 170–
230 mg/dL, depending on the control time. Similar results were
obtained by other authors [288] with the methanolic extract of this
plant, also collected in Iran. In this case, the glucose level reduction
observed in rat blood was accompanied by an increase in the insulin
secretion in C187 pancreatic β-cells. Additionally, a reduction in lipidic oxidation was proved by the decrease in MDA values and the increase in GSH values. The ethanolic extract of O. persica was demonstrated to possess protective effects by preventing renal damage induced by ischemia/reperfusion induced in diabetic rats
[289]. The hematic renal function indicators were ameliorated
after treatment with 300 mg/kg b. w. of the extract for 2 wk: urea
from 67.6 to 36.1, creatinine from 2.32 to 1.32, glucose from 378.6
to 147.2. Furthermore, kidney resection and tissue evaluation of
the oxidative stress parameters (MDA, MPO, NO, SOD, and CAT)
evidenced a beneficial effect in O. persica treated animals.
The antidiabetic activity of the AP of O. persica were assessed in
different factions of the crude extract, following their solubility in
PE, CHCl3, EtOAc, n-BuOH, and MeOH [141]. The antioxidant activity was measured by DPPH method and was correlated to antidiabetic activity in mice. MeOH extract was effective in reducing
hematic glucose with a 300 mg/kg b. w. dose. Both MeOH an
EtOAc extract showed antioxidant activity with IC50 of 0.49 mg/
mL for both. Finally, 4 compounds were isolated from the active
extracts: chrysoeriol (91) from EtOAc, 6-methylapigenin (77), api-
genin-7-O-β-D-glucopyranoside (112), and echinaticin (138)
from the MeOH one.
The aerial part of O. persica also showed a potent antidiabetic
effect when extracted in water at 40 °C [290]. Fasting blood sugar,
insulin, and HOMA.IR (homeostasis model assessments for insulin
resistance) were evaluated in STZ-induced diabetic mice after 10,
20, and 30 d of administration of up to 400 mg/kg b. w. of the extract. The indicator improvements were comparable to those reported in other studies, and total cholesterol and triglycerides
were also significantly reduced: 95 versus 75 mg/dL for the former
and 203 versus 71 for the latter. A reduction in the number and
the mass of pancreatic β-cells was evidenced by histopathological
visualization techniques.
The antidiabetic effect of O. persica (AP extracted in EtOH/H2O
1 : 1) was also studied by stereological analysis of pancreas tissue
in diabetic (STZ induction) Sprague-Dawley rats [291]. The oral
administration of 500 mg/kg b. w. reduced blood glucose levels
and insulin production, as reported in many other references.
After 1 mo, the animals were sacrificed and pancreatic tissue was
analyzed. A hypertrophic change in the remaining β-cells of the
diabetic group was observed, accompanied by a reduction in pancreatic islet volume. These phenomena were significantly reduced
in the animals treated with the extract.
B. aucheri extract (AP in 70 % MeOH) [232] was effective in reducing postprandial hematic glucose increment in type II diabetic
rats, while it was ineffective in type I diabetic animals. This antidiabetic activity was associated with a notable antioxidant activity
determined in this sample (▶ Table 13).
Bone damage such as osteoporosis may constitute an important comorbidity in patients affected by mellitus diabetes. The
aqueous extract of O. persica (Iran) was proven to act as a protection from bone damage in STZ treated diabetic rats [292]. Rats
was treated orally with 200–450 mg/kg b. w. for 29 d. Then the
left femoral and tibiofibular bones were dissected and evaluated
histomorphometrically, while the right-side bones were removed
for ash weight determination. The plant extract was able to significantly reverse the epiphyseal and metaphyseal trabecular width
reduction observed in untreated animals. Additionally, the epiphyseal bone area/tissue were normalized with the utilization of the
minimum extract dose. Ash weight was significantly lower in animals treated at 450 mg dose.
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▶ Table 13 Continued
Species
Origin
Sample preparation
(plant part: solvent)
Test
Target
Ref
B. acetabukosa
Turkey
L: EtOH 80 %, W
MIC, MBC (µg/mL): 0.4–
1.6; 3.2–12.5 (EtOH), 0.8–
3.2, 6.3–12.5 W
S. aureus
[249]
B. acetabukosa
Turkey
L: EtOH
MIC (mg/mL) 32–1024;
MBC (µg/mL) 64–1024.
E. faecalis, E. coli, P. mirabilis, K. pnemoniae,
P. aeruginosa
[250]
B. africana
S. Africa
L: MeOH, W
MIC (µg/mL) 438
K. pneumoniae, A. nauplii
[251]
B. andreuzziana
Libya
WP: EtOAc, CHCl3, BuOH, W
AD at 50, 100, 150 mg/mL
(mm) 7–11
S. aureus, B. subtilis, My phlei
[148]
B. deserti
Algeria
EO
L: MeOH
MIC biofilm formation EO
(µL/mL) 25–80; MeOH
(mg/mL) 3.25–25
S. aureus (ATCC 25923, ATCC 6538-P), S. epidermidis, [204]
B. subtilis, B. cereus, S. mutans, M. luteus
B. deserti
Algeria
AP: CH2Cl2, MeOH; then isolat.
compds: 40, 223, 227
MIC (µM): 46–162
E. faecalis, P. aeruginosa, S. aureus
[90]
B. inaequidens
Turkey
AP: Ac; isolat. compds: 5, 25,
79, 103, 105, 107, 108, 109
MIC (µg/mL): 25–50
S. aureus, B. subtilis, E. coli, P. aeruginosa
[76]
B. nigra
Italy
S: EtOH
Quantification of δ-hemo- S. aureus
lysin. Response in the production of δ-hemolysin, indicating anti-QS activity in a
pathogenic MRSA isolate.
No inhibitory effect
B. nigra
Pakistan
S, L, R: EtOH then part. between AD at 5 mg/mL (mm) 8–30
W and n-Hex, EtOAc, CHCl3,
BuOH
E. coli, S. aureus, P. mirabilis, K. pneumoniae, E. faecalis, [253]
S. typhi
B. nigra
Serbia
S, L: EO
MIC (µg/mL): 2.5–5
E. coli, S. aureus, B. mycoides, M. lysodeikticus,
B. subtilis, K. pneumoniae, C. albicans
[209]
B. nigra
France
shoots: 50 % EtOH then isolat.
compds: 220, 223, 227
MIC (µg/mL): 64–128
S. aureus, S. aureus MRSA, P. mirabilis
[187]
B. nigra
Italy
WP: W
MIC, dose-dependent biofilm formation inhibition,
max inhib. at 128 µg/mL
S. aureus MRSA
[254]
B. nigra spp.
anatolica
Turkey
L: EtOH
MIC (µg/mL) 250–1000
B. subtilis, B. cereus, S. aureus, E. coli, P. vulgaris,
S. typhimurium, P. aeruginosa
[255]
B. nigra spp.
anatolica
Turkey
L: EtOH
AD at 50 µg/mL (mm)
10.0–19.2
B. cereus, P. aeruginosa, K. pneumoniae, S. capitis,
S. aureus, S. epidermidis, P. acnes, M. nonliquefaciens,
[256]
B. nigra ssp
foetida
Italy
EO
MIC, MBC (mg/mL): 3–7
E. coli, E. cloacae, P. aerouginosa, F. fluorescens,
S. aureus, S. epidermidis
[216]
B. pseudodictamnus
Pakistan
S, L, R: EtOH then part. bet.
W/n-Hex, EtOAc, CHCl3, BuOH
AD at 2 µg/mL (mm)
0.8–20
E. coli, S. aureus, P. mirabilis, K. pneumoniae, E. faecalis, [257]
S. typhi
B. pseudodictamnus
Greece
EO
MIC (mg/mL) 0.45–10.15,
> 20 for E. coli
S. aureus, S. epidermidis, E. coli, E. cloacae,
K. pneumoniae, P. aeruginosa
[220]
B. rotundifolia
Turkey
WP: MeOH then the extract
was split in W-soluble and
W-insoluble fractions
MIC (µg/mL): > 72
S. pneumoniae, B. cereus, A. lwoffii, E. coli,
K. pneumoniae, C. perfringens
[238]
B. saxatilis
Turkey
F: Ac: then isolat. compds:
5, 18, 25
MIC (µg/mL): 25–50
S. aureus, S. faecalis, E. coli, P. aeruginosa,
K. pneumaniae.
[80]
B. saxatilis ssp.
brachyodonta
Turkey
EO
MIC (µg/mL): 25–50
E. coli, E. feacalis, B. subtilis, S. thyphimurium, S. aureus, [221]
S. epidermidis, K. pneumoniae
O. fruticosa
Egypt
EO
MIC (µg/mL): 1.5–6
B. subtilis, S. aureus, E. coli, S. epidermidis, S. faecalis,
K. aerogenes
[224]
O. fruticosa ssp.
schimperi
Yemen
EO
MIC (µg/mL): 310–1250
B. cereus, S. aureus, E. coli, P. aeruginosa
[222]
O. integrifolia
Ethiopia
L: 80 % MeOH, CHCl3
MIC (mg/mL): 0.312
M. tuberculosis
[258]
cont.
Rosselli S et al. A Review of …
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[252]
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▶ Table 14 Antibacterial activity of Ballota and Otostegia taxa.
Reviews
Species
Origin
Sample preparation
(plant part: solvent)
Test
Target
Ref
O. integrifolia
Ethiopia
EO
MIC (mg/mL) 5–100
E. coli 18/9, E. coli ATCC 10536, E. coli CD/99/1,
E. coli K88, E. coli RP4, E. coli VC Sonawave 3 : 37 C,
P. aeruginosa, S. boydii, S. dysentery, S. flexneri,
S. soneii 1, S. soneii BCH 217, V. cholera, B. subtilis
[56]
O. limbata
Pakistan
WP: 70 % EtOH. then ext.
solubilized in DMSO, EtOH,
MeOH
MIC (mg/mL): 0.2–5
B. subtilis, L. monocytogenes, S. aureus, E. coli,
P. aeruginosa, Salmonella spp.
[259]
O. persica
Iran
AP: MeOH
MIC (mg/mL): 0.5–2
E. coli, B. subtilis, S. aureus, S. epidermis, P. aeruginosa, [260]
S. typhi, K. pneumonia, A. niger
O. persica
Iran
AP: 70 % EtOH, n-Hex, CHCl3,
MeOH
MIC (mg/mL): 1.25–25
E. coli, L. monocytogen, E. faecalis, S. aureus,
S. epidermidis, B. subtiltis, P. aeruginosa,
Salmonella spp. Klebsiella spp.
The Ethiopian plant O. integrifolia, in particular the leaf extract
in 80 % MeOH, was also effective in contrasting diabetes in mice
and rats [293]. STZ induced diabetic mice receiving doses from
100 to 400 mg/kg b. w. of extract displayed time-dependent hypoglycemic effects. After 4 h, the dose of 200 mg reduced the
hematic glucose from 375 to 159 mg/dL.
Three extracts were obtained from the AP of B. cinerea (India)
by brewing them in PE, EtOAc, and MeOH [294]. They were active
in reducing blood glucose levels in diabetic rats both with acute
(after 4 h) and with chronic (after 21 d) alloxana-induced disease.
Total reduction of glucose reached values (36–42 %) comparable
to the standard antidiabetic drug glibenclamide. Other authors
[267] reported slightly different values for the activity of the same
extracts, together with the EtOH extract, assessed in the reduction of hematic glucose in STZ-induced diabetic rats: from 18.2
to 23.4 % reduction after 24 h at 100 mg/kg b. w. Furthermore,
similar results in reducing murine glycemia were obtained with
the butanol and water extract of the same taxon [233]. In the last
study, the lipidic profile, the hepatic glycogen content and the
pancreatic parameters (SOD, GSH, and PGx) were also evaluated
after 15 d of extract treatments at 50 mg/kg b. w. Almost all of
the parameters were normalized as compared to standard values,
and these beneficial effects were confirmed by the histopathological evaluation of pancreatic and hepatic tissue dissections. Take
note that the dose of extract implemented in this study is significantly lower than the average doses normally utilized in similar
contexts.
4-Methoxybenzo[b]azet-2(1H)-one (214) and 3β-hydroxy-35(cyclohexyl-5′-propan-7′-one)-33-ethyl-34-methyl-bacteriohop16-ene (178), isolated from the aerial part of B. cinerea (India)
[182], significantly reduced the blood glucose level in alloxan-induced diabetic rats at the dose of 10 mg/kg b. w. administered
orally.
An interesting protective effect for hyperlipidemia was investigated for the aqueous extract of B. arabica (syn. L. urticifolia) in a
Triton WR-1339 induced hyperlipidemic rat model [295]. The administration of a 100–400 mg/kg b. w. dose for 24 h was able to
restore normal values of plasma lipidic parameters, total cholesterol, TG, LDL, VLDL, and to significantly raise the HDL level.
[261]
Other bioactivities in vivo
The fruit extract of B. undulata obtained in EtOH/water 7 : 3 was
shown to be effective as a fertility controller in Albino rats [296].
The effects were time dependent: after a treatment of 4 wk at
15 mg/kg b. w. per day, the numbers of pregnancies was not reduced significantly, while only a slight reduction in embryo and
ovarian weights was observed. On the contrary, when the treatment was prolonged until 12 wk, the percentage of embryo implantation and pregnancies with respect to the controls was statistically relevant.
The extract of O. persica AP in MeOH was tested for its healing
promoting activity in the skin of Wistar rats [297]. The healing
process of burns provoked in the dorsal part of animals was accelerated by the application of a ointment in which the extract was
dispersed. The histological evaluation evidenced an increase in fibroblast proliferation, angiogenesis and re-epithelialization that
improved in a 5- to 14-d time range.
Ischemia-reperfusion is a dangerous syndrome that can cause
severe injuries to remote organs, due to multiple effects, including the increase in reactive oxygenated radicals and general inflammation conditions. The ethanolic extract of O. persica (Iran)
demonstrated protective effects toward renal injury in rats suffering of a hindlimb ischemia reperfusion surgically induced by
clamping the femoral artery [298]. Reperfusion induced kidney
damage including the increase of water uptake, creatinine excretion rate, and kidney/body weight. The animals treated with
300 mg/kg b. w. of extract 2 d before intervention had the abovementioned renal functionality parameters at levels comparable
with the negative control.
The antihypertensive effect of the AP extract (70 % EtOH) of
O. persica was proven in Wistar rats suffering from dexamethasone-induced hypertension [299]. The systolic pressure increase
from 115 to 143 mmHg was completely suppressed by a dose of
400 mg/kg b. w. per day of the extract, administered 2 d before
starting the dexamethasone treatment. The hematic H2O2 and
FRAP values increased by dexamethasone were also normalized
in the animals receiving the plant brew.
Rosselli S et al. A Review of …
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▶ Table 14 Continued
Species
Origin
Sample preparation
(plant part: solvent)
Test
Target
Ref.
B. acetabulosa
Turkey
L, R: 50 % EtOH
MIC (mg/mL) 1.56–25.0
C. albicans, C. tropicalis, C. guilliermondii,
Cryptococcus neoformans, C. laurentii
[263]
B. deserti
Algeria
EO
L: MeOH
MIC biofilm formation EO
(µL/mL) 25; MeOH extr,
(mg/mL) 12.5
C. albicans
[204]
B. inaequidens
Turkey
AP: Ac; then isolat.
compds: 5, 25, 79,
103, 105, 107, 108,
109
MIC (µg/mL) 3.1–12.5
C. albicans, C. crusei
[76]
B. nigra
Paikstan
S, L, R: EtOH then
partition between
W/n-Hex, EtOAc,
CHCl3, BuOH
Agar tube diluition, results A. niger, A. flavus, A. fumigatus, F. solani
reported as inhibition
“positive” or “negative”;
crude extrat always positive at 2 mg/mL
[253]
B. nigra ssp. anatolica
Turkey
L: EtOH
MIC (µg/mL): 500–1000
C. albicans, D. hansenii, K. fragilis, R. rubra
[255]
B. nigra ssp foetida
Italy
EO
MIC (mg/mL) 5.5;
MBC (mg/mL) 15.0
C. albicans, C. glabrata, C. tropicalis
[216]
B. pseudodictamnus
Pakistan
S, L, R: EtOH then
partition between
W/n-Hex, EtOAc,
CHCl3, BuOH
Agar tube dilution, results A. niger; A. fumigates, A. flavus; F. solani
reported as inhibition
“positive” or “negative” at
2 mg/mL
[257]
B. pseudodictamnus
Greece
EO
Not active
C. albicans, C. tropicalis, C. glabrata
[220]
B. rotundifolia
Turkey
WP: MeOH then the
extract was split in
W-soluble and
W-insoluble fractions
MIC (µg/mL) > 72
C. albicans, C. krusei
[238]
B. saxatilis
Turkey
L: Ac then isolat.
compds: 5, 18, 25
Agar diluititon MIC
(µg/mL): 1.5–3.1
C. albicans
[80]
B. saxatilis ssp.
brachyodonta
Turkey
EO
MIC (µg/mL): 25
C. albicans (clinic strain), C. parapsilosis
[221]
B. undulata
Egypt
L, S, F: EtOH, EtOAc,
CHCl3, n-Hex
MIC (mg/mL): 25 – > 150
T. rubrum, T. tonsurans, C. albicans,
C. tropicum, P. lilacinus, P. variotii,
S. bervicaulis
[264]
O. integrifolia
Ethiopia
EO
MIC (µg/mL): 50–100
A. niger, C. albicans, P. funiculosum,
P. notatum
[56]
O. fruticosa
Egypt
EO
MIC (µg/mL): 6.0, 16.0
C. albicans, S. cerevisiae
[224]
O. limbata
Paikstan
WP: MeOH, then
partition in n-Hex,
CHCl3, EtOAc, BuOH
MIC (mg/mL) 0.18–1.5
S. setubal, P. pickettii, S. aureus, M. luteus
[265]
O. persica
Iran
AP: MeOH
MIC (mg/mL): 1.0
C. albicans
[260]
Anti-malarial activity
A significant antimalarial effect in Plasmodium berghei Vinke &
Lips-infected mice was disclosed for O. integrifolia collected in
Ethiopia [300]. Mice were administrated with 200, 400, and
800 mg/kg b. w. doses of the leaf extract prepared in chloroform,
MeOH, and water. The survival of the animals treated with polar
extract was dose-dependent and significantly higher than that of
the negative control (10.5 vs. 7.5 d of H2O ext. at max. dose; 13.5
vs. 7 for MeOH ext.). General lack of toxicity was proven until
reaching a 2000 mg/kg b. w. dose. Also in this case, the very high
dose of extract employed may be an obstacle for possible developments toward application to humans. However, a study appear-
Rosselli S et al. A Review of …
Planta Med
ing in the literature in the same year [101] resulted in the bioguided isolation of the labdane diterpene otostegindiol (43) from
the methanolic extract of O. integrifolia leaves. This compound
showed chemosuppressive properties against P. berghei with a
maximum suppression ratio of 73.16 % at 100 mg/kg. Additionally, the EtOH extract of the aerial part of Iranian O. persica [301]
demonstrated antimalarial activity in P. berghei infected mice with
ED50 of 45 mg/kg b. w. Furthermore, an interesting synergistic effect was observed when CQ-sensitive animals were treated with a
combination of this drug and the plant extract; for example, a
combination of 70 % of the ED50 of CQ with 30 % of extract caused
a 26 % increase in the mean effective dose.
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▶ Table 15 Antifungal activity of Ballota and Otostegia taxa.
The effective antiprotozoal activity against another relevant
malarial parasite, Plasmodium falciparum Welch, was disclosed in
both the PE and the chloroform extracts of B. cinerea from India
[302]. The IC50 values for the 2 materials were 4.39 and 1.84 µg/
mL, respectively.
Hepatoprotective effects
The AP extract (80 % MeOH) of O. persica collected in Iran [303]
was effective in strongly reducing liver damage in CCl4 intoxicated
rats (2.5 mg/kg b. w.). After administrating 400 mg/kg b. w. of extract, hematic liver damage parameters were significantly ameliorated with respect to untreated animals: ALT 13 %, AST 11.6 %,
plasma MDA 6.7 %, liver MDA 11.4 %, liver GSH + 21 %. Histological
evaluation of liver sections demonstrated the prevention of tissue
degradation in treated rats. A similar protective effect was described for the aqueous extract of the AP of B. glandulosissima
from Turkey [245]. Liver damage indicators in the blood of CCl4treated rats (0.8 mL/kg b. w.) were reduced significantly with
100 mg/kg b. w. of extract: AST 59 %, ALT 47 %, ALP 43 %, bilirubin
47 %. The efficacies of the 2 above-cited treatments are hardly
comparable considering the differences in applied dose intoxication, in the extraction procedure and in the feeding procedures
of the animals involved in these studies. Similar protective effects
on the liver were found in the AP extract (70 % MeOH) of O. persica
collected in Iran [304] administrated to rats at 80–120 mg/kg
b. w.
The hepatoprotective effect of B. cinerea (syn. Roylea elegans
Wall. ex Benth.) collected in India was assessed for the AP extract
obtained in EtOH/H2O 1 : 1 in a CCl4 and paracetamol toxicity induced model in rats [305]. Hepatic damage was evaluated by several blood parameters, such as SGOT, SGPT, ALP, and TB, after
treatment with 100–400 mg/kg b. w. of extract for 7 d. Also, the
liver oxidative stress indicators GSH and TBARS were followed.
The pathological displacement of all of the indicators was reduced
in a dose-dependent fashion and complete normalization occurred at the dose of 400 mg.
Enzymatic activity modulation
There are a number of investigations aimed at evaluating the
plants from Ballota and Otostegia genera as a source of useful bioactive compounds isolated from the complex blend of their secondary metabolites. The extract of O. limbata root in MeOH led
to the isolation and identification of 3 new tricyclic cis-clerodane
diterpenes: limbatolide A (64), limbatolide B (65), and limbatolide
C (66) that were assessed of their inhibitory potential against acetylcholinesterase (AChE; EC 3.1.1.7) and butyrylcholinesterase
(BChE; EC 3.1.1.8). The inhibition activity was higher for the latter
enzyme (IC50 22.3, 17.5 and 14.2 µM, respectively) than for the
former (IC50 38.5, 47.2, and 103.7 µM) [112]. These enzymatic
systems were also the targets of another similar work concerning
the isolation of 6 clerodane tricyclic diterpenes from the chloroform extract of B. limbata [107]: ballatenolide A (59), 15-methoxypatagonic acid (71), patagonic acid (72), and limbatenolides A–C
(54–56). All of the compounds showed inhibitory activity with
BChE with IC50 values ranging from 24.9 to 51.0 µM, lower than
the standard inhibitor galanthamine (8.5 µM). The first group of
3 compounds also showed a moderate inhibitory activity with
AChE with IC50 values between 50.0 and 102 mM (galanthamine
0.50 µM). The inhibition activity toward the 2 enzymatic systems
was also assessed with the MeOH extract of the aerial part of
B. deserti from Algeria [204], obtaining moderate IC50 values:
277.4 µg/mL for AChE and 93.3 µg/mL for BChE.
Ballotenic acid (60) and ballodiolic acid (62) were isolated from
the chloroform soluble fraction of the MeOH extract of B. limbata
[110] and displayed inhibitory potential against lipoxygenase enzyme in a concentration-dependent fashion with IC50 values of
99.6 µM and 38.3 µM, respectively.
Furthermore, the crude n-Hex extract of B. nigra subsp. kurdica
[306] from Iran was investigated for its possible tyrosinase inhibitory activity by the colorimetric Tyrosinase inhibition assay
(IC50 = 3.67 µg/mL); however, no attempt was made to isolate individual active molecules.
Tyrosinase was also effectively inhibited by 2 compounds isolated from the AP extract of B. cinerea from India [182]: 4methoxybenzo[b]azet-2(1H)-one (214) and 3β-hydroxy-35-(cyclohexyl-5′-propan-7′-one)-33-ethyl-34-methyl-bacteriohop-16ene (178) with inhibition rate of 83.0 and 58.2 %, respectively, at
100 µM. These compounds were also effective inhibitors of α-glucosidase (78.5 % and 58.4 %). This inhibitory activity is related to
the above discussed antidiabetic activity in vivo of these compounds. The α-glucosidase and β-glucosidase reduction activities
were evaluated in a study on the antidiabetic activity in vitro and in
vivo of some extracts of B. cinerea from India [294]. Three fractions
were found more active, respectively, obtained with PE, EtOAc,
and MeOH; their activity reduction power ranged about from 55
to 80 %, with the MeOH extract being the most active. In another
work [267], these extracts were tested in an in vitro inhibitory activity test against protein tyrosine phosphatase-1B, showing results ranging from 39 to 65 % inhibition at 100 µM.
α-Amylase, an enzyme involved in saccharide metabolism
which is believed to possess preventive properties for type II diabetes, is strongly inhibited by polyphenolic compounds [307]. For
this reason, the inhibitory activity of the extracts of O. persica was
evaluated in association with the antioxidant activity (DPPH test,
see ▶ Table 13) [243]. The initial crude extract obtained in EtOH
was then partitioned in solvents of different polarities: PE, EtOAc,
CHCl3, n-BuOH, EtOH. The enzymatic parameters were measured
for all of the fractions: inhibition rate from 53.3 (pet. Ether) to
99.4 % (EtOAc). The author attempted to relate the total phenolic
content of the extracts both with the antioxidant and the enzyme
inhibition activity.
The 2 new flavonoidal glucosides leufolins A (163) and B (152)
isolated from B. arabica (syn. L. urticifolia) have shown to be potent
inhibitors of BChE enzyme (IC50 values 1.6 and 3.6 µM, respectively) when compared to serine, used as a positive control (IC50
0.93 µM). On the other hand, very weak activity was observed
against acetylcholinestrase (IC50 values 74.5 and 72.3 µM, respectively), compared to eserine (IC50 = 0.04 µM) [171]. The new steroid leucisterol (179), also isolated from the same species,
showed potent inhibitory activity against butyrylcholinesterase
enzyme (IC50 = 3.2 µM). [181].
Rosselli S et al. A Review of …
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Reviews
In this review a complete recognition of the volatile and not volatile secondary metabolites occurring in the Ballota and Otostegia
genera has been carried out. The 13C NMR data of diterpenes reported in literature have been collected for comparison purposes
in structural determination. Some relevant studies on several biological activities have been reported that include antioxidant,
anti-inflammatory, antibacterial, antifungal, antitumor, and antidiabetic.
Acknowledgements
This work was supported by grant from MIUR-ITALY PRIN 2015 (Project
N. 2015MSCKCE_003) and PRIN 2017 (Project N. 2017A95NCJ).
Conflict of Interest
The authors declare that they have no conflict of interest.
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