Fitoterapia 134 (2019) 23–38 Contents lists available at ScienceDirect Fitoterapia journal homepage: www.elsevier.com/locate/fitote Review Biological activity, phytochemistry and traditional uses of genus Lobelia (Campanulaceae): A systematic review T Daniela G. Folquittoa, , Juliane N.D. Swiecha, Camila B. Pereirab, Vanessa B. Bobeka, Gerusa C. Halila Possagnob, Paulo V. Faragob, Marilis D. Miguela, Juliana L. Duartec, Obdulio G. Miguela ⁎ a Graduate Program in Pharmaceutical Sciences, Federal University of Paraná, Avenida Pref. Lothário Meissner, 632, Curitiba, PR CEP.: 80210-170, Brazil Graduate Program in Pharmaceutical Sciences, State University of Ponta Grossa, Av. General Carlos Cavalcanti, 4748, Ponta Grossa, PR CEP.: 84030-900, Brazil c Graduate Program in Pharmaceutical Sciences, Higher Education Center of Campos Gerais, Rua Tomazina, S/N, Olarias, CEP.: 84025-510 Ponta Grossa, PR, Brazil b 1. Introduction 2. Materials and methods The genus Lobelia L. (Campanulaceae) was named by PLUMIER in honor of Mathias de L'Obel in 1538 and comprises 415 species distributed worldwide [1,2]. Lobelia species have been used traditionally for treating various diseases, L. inflata L., widely used in the form of powder, tincture, syrup, and infusion, received more attention from scholars owing to its emetic, hypnotic, anti-asthmatic, and astringent properties. L. siphilitica L.; was used by indigenous people in Canada as an anti-syphilitic, L. urens L. from Europe was employed as vermifuge, L. laxiflora Humb. was used as an emetic, expectorant, and breathing regulator, L. tupa L. was used in ophthalmology, and L. purpurascens R. Br. was used in the treatment of snake bites [1]. Studies on the therapeutic properties and isolation of active principles began in 1885, and it triggered several references for other studies on alkaloid-producing species [1,3,4]. They are a valuable source for the extraction of pharmacologically active compounds, in particular, piperidine alkaloids, which have several pharmacological properties [5–9]. The isolated piperidine alkaloids include lobeline, lobelane, lobelanidine, norlobelanine, and lobelanine. Other secondary metabolites such as flavonoids, terpenes and triterpenes, saponins, and coumarins have also been isolated [10–12]. There are also other reports in the literature on the anti-inflammatory, anticonvulsant, analgesic, and antimicrobial activities of phytosterols such as sitosterol, stigmasterol, and campesterol, and αand β-amyrin [13–23]. This systematic review documents existing knowledge about the traditional uses, phytochemistry, and biological research of species belonging to the genus Lobelia. In this review, we aimed to provide a comprehensive overview of the phytochemistry and pharmacology of the genus Lobelia to show the presence of important metabolites and help to point future discoveries related to species of this genus. The protocol for performing this study was developed following the PRISMA statement (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) [69]. All steps were conducted by two independent reviewers and discrepancies were resolved by a third reviewer. ⁎ 2.1. Data sources The literature search was performed using the following databases: MEDLINE (via PubMed), Embase, Lilacs, IPA, Scopus, Web of Science, Scifinder, OVID SP, Science Direct, Isi Web of Knowledge, and Scielo, over the period from the beginning of the database until May 2017. The following descriptors were used in the search: “Lobelia,” “traditional uses of lobelia,” “alkaloid,” “neurology,” “phytochemical,” “chemistry,” “Parkinson,” “degenerative diseases,” “degenerative disorders,” “antitumor,” “anticancer,” “chemical compounds, “chemical constituents,” “biological activities,” “antimicrobial,” “antibacterial,” “antifungal,” and “pharmacological.” In addition, as a second search strategy, we included studies obtained by manual search of the reference lists of the included studies. There was no search for unpublished literature data or conference proceedings. 2.2. Study selection Articles on the species of the genus Lobelia that reported biological activities, traditional uses, and isolation and identification of chemical constituents were included. The exclusion criteria were as follows: (1) Any publication where the full text was not available in the database or even after contacting the author by email; (2) articles that did not present the search terms in the title and abstract; (3) articles that described reviews or systematic reviews; and (4) articles in which the chemical constituent used to perform the biological activity was not isolated in the study, but rather Corresponding author. E-mail addresses: danielafolquitto@gmail.com, daniela.folquitto@cescage.edu.br (D.G. Folquitto), obdulio@ufpr.br (O.G. Miguel). https://doi.org/10.1016/j.fitote.2018.12.021 Received 17 September 2018; Received in revised form 18 December 2018; Accepted 29 December 2018 Available online 18 January 2019 0367-326X/ © 2019 Elsevier B.V. All rights reserved. Fitoterapia 134 (2019) 23–38 D.G. Folquitto et al. Recording of articles identified through database search (n=249) Excluded (n=107) Articles included and Excluded (n=69) evaluated in their entirety Did not meet the protocol criteria (n=93) Additional studies obtained Articles included (n=26) Fig. 2. General structure of piperidine alkaloids. by manual search (n=8) were found irrelevant based on the title or abstract. The other 93 articles went to the next phase and were read in full. Only 26 articles were included because 69 articles did not meet the inclusion criteria. A flowchart of the results obtained and the reasons for not selecting the articles are presented in Fig. 1. The complementary manual search selected 8 articles, and therefore, in total, 34 articles were included in the study. Total of articles included (n=34) Fig. 1. Flowchart of reviews included and excluded. commercially acquired. After obtaining the articles, all stages of the process were performed by two independent reviewers (DGF and CBP), and any discrepancies were resolved by consensus. In the absence of an agreement, the assistance of a third reviewer (JNDS) was requested. The process of study selection followed the PRISMA Model: (a) All the articles obtained were analyzed based on the titles and abstracts (screening); (b) The articles considered relevant were analyzed in their entirety by the two reviewers, observing the inclusion and exclusion criteria (eligibility); (c) Articles that met all the criteria were included for data collection (inclusion). The articles that generated doubt in the screening phase were included and passed to the eligibility phase for complete analysis. All selected articles were read in full. Data related to biological activities, methods of extraction, isolation and identification of chemical constituents, primary outcome measures, and results were extracted by the first author and validated by the second author. 3.1. Traditional uses Since ancient times, Lobelia species have been used in folk medicine worldwide in the form of infusions and tinctures for the treatment of various diseases. The most commonly cited traditional use of Lobelia inflata L. (known as “Indian Tobacco”) is smoking cessation and for the treatment of respiratory diseases such as asthma and bronchitis [1,4,5,24–26]. In Ayurveda, a decoction of flowers of Lobelia nicotianaefolia Roth E is used for asthma, bronchitis, and fever; roots for eye disease; and leaves for rapid wound healing. Moreover, it has been traditionally used to treat pain and snakebites [13,27,28]. The alkaloids present in Lobelia polyphylla Hook & Arn., a Chilean species, is probably involved in the toxic, narcotic, and hallucinogenic effects produced after smoking or consuming the aerial parts of this species. Lobelia tupa, also known as “devil's tobacco,” contains a poisonous and caustic latex that causes vomiting, intestinal irritation, and delirium if ingested [29]. The leaves and inflorescences of Lobelia. pyramidalis Wall, an Indian species, are used as an antispasmodic and for the treatment of asthma, bronchitis, fever, sciatica, and back pain [30]. The dry leaves of Lobelia flaccida Persl. are used as analgesics and antiepileptics in the Eastern Cape region of South Africa [31]. Another native American species known for its medicinal potential is Lobelia. cardinalis L. Plant formulations are consumed for various purposes, for example, as an emetic, in the treatment of typhoid and fever, and as a “love potion” [32]. 2.3. Data extraction The data of interest in each study were as follows: periodical; collection site of the plant; traditional uses of lobelia; isolated substances, and biological activities. Disagreements were resolved by consensus among reviewers. 3. Results By searching the databases, we found 249 articles of potential relevance, of which 107 were duplicates and 49 were discarded as they Table 1 Geographic location and uses of Lobelia species. Binomial Uses Geographic location References L. cardinalis L. chinensis Lour Eastern of North America China [32] [7,11,33–37] L. flaccida Emetic, typhoid, fever, and “love potion” Diuretic, hemostatic, antimicrobial, antiviral, anti-inflammatory, edema, jaundice, liver, stomach, intestinal diseases, antitumor Analgesic, antiepileptic [31] L. L. L. L. L. L. L. respiratory stimulant, emetic, to tobacco smoking cessation Asthma, bronchitis, fever; eye disease; and leaves for rapid wound healing Narcotic and hallucinogen Antispasmodic, asthma, bronchitis, fever, sciatica, and back pain Phlegm, cough, cirrhosis ascites, abscess, and snakebite Cathartic, diaphoretic, emetic, treatment of dropsy, diarrhea, stomach complaints, syphilis and dysentery Abortifacient, hallucinogen, respiratory stimulant, to tobacco smoking cessation Eastern Cape region of South Africa Eastern North America India Chile India China Eastern North America Chile inflata nicotianaefolia polyphylla pyramidalis sessilifolia siphilitica tupa 24 [1,4,5,24–26] [29] [30] [54] [29] Fitoterapia 134 (2019) 23–38 D.G. Folquitto et al. OH OH OH OH H3C N N CH3 CH3 OH CH3 (5) Lobelanine [40,42,26] O OH OH N O N (4) Lelobanidine [39] (3) Lobelanidine [6,26,39–41] O O CH3 O N H N H CH3 (6) Lobeline [6,13,26,29,40,42–44] (7)Norlobelanidine [29,41,45] (8) Norlobelanine (=Portoricin) [26,40–43,46] OH OH CH3 N (11) [N-methyl-2,6-bis(2hydroxybutyl)- -piperidine] [10,35] CH3 (10) 8-phenylnorlobelol [49] (9) Lobinaline [32,47,48] OH OH H3C N CH3 N N H N OH OH H3C O H3C CH3 O CH3 N OH H3C N CH3 CH3 CH3 (12) [N-methyl-2- (2hydroxypropyl)-6-(2hydroxybutyl)- -piperidine] [10,35] (13) [N-methyl-2-(2-oxobutyl)-6– (2piperidine][10,35] (14) Lelobanonoline [29,41] OH OH OH HO OH OH H3C N OH N H CH3 O CH3 HO (15) cis-8,10-diethyl-1-3,4dehydrolobelidiol, [50,51], (16/17) trans/cis-8-ethyl-10phenyl-3,4-dehydrolobelidiol [50,51] HO (18) 7-O- –D-glucopyranosylhomonojirimycin [52] OH O CH3 H N HO O HO CH3 N OH OH H3C H N HO OH O OH N H OH HO (19) Radicamine A [33] OH HO (20) Radicamine B [33] (21) Norlobeline [26] Fig. 3. Structures of the alkaloids isolated from Lobelia sp [45]. stomach tumors [7,11,33–37]. Lobelia sessilifoilia Lamb is another Chinese species that is used in Chinese folk medicine for the treatment of phlegm, cough, cirrhosis ascites, abscess, and snakebite phlegm, cough, cirrhosis ascites, abscess, and snakebite [54]. Lobelia chinensis Lour. is a species that shows to have diuretic, hemostatic, antimicrobial, antiviral, and anti-inflammatory activities. In addition, it is used as an antidote for poisons and for the treatment of edema, jaundice, liver, stomach, and intestinal diseases, and breast and 25 Fitoterapia 134 (2019) 23–38 D.G. Folquitto et al. HO HO O O O O OH N H N CH3 (22) 3-hydroxy-3-phenylpropanoic norallosedamine [26] (23) 3-hydroxy-3phenylpropanoic allosedamine [26] H3C O N CH3 CH3 24) 8,10-dietillobelidione [46] Fig. 3. (continued) cardinalis L., Lobelia puberula Michx., Lobelia yuccoides Hillebr., Lobelia portoricensis (Vatke) Urb., Lobelia polyphylla Hook & Arn., Lobelia berlandieri A. DC., Lobelia davidii Franch., Lobelia laxiflora L., Lobelia sessilifolia Lamb., Lobelia inflata L., Lobelia erinus L. and Lobelia chinensis Lour, led to the discovery of different classes of secondary metabolites. The alkaloids were presents in most of the species (46.05%), followed by flavonoids (25%), terpenoids (13%), polyacetylenes (5.25%), coumarins (4%), fatty acids (4%), neolignans (1.35%), and amides The Table 1 shows the uses of some species of Lobelia genus that were possible to verify in researched articles. 3.2. Phytochemical investigation Phytochemical researches of Lobelia species named Lobelia giberroa Hemsl., Lobelia siphilitica L., Lobelia nicotianaefolia Roth E. and S., Lobelia salicifolia Sweet, Lobelia tupa L., Lobelia urens L., Lobelia 26 Fitoterapia 134 (2019) 23–38 D.G. Folquitto et al. CH3 CH3 H3C CH3 H CH3 H CH3 H3C CH3 CH3 H CH3 CH3 H HO H CH3 H3C HO –amyrin [7,41] (38) HO –sitosterol [41,53] (37) Stigmasterol [7] H3C CH3 H3C H CH3 H O H3C H3C H3C CH3 CH3 H CH3 HO CH3 (40) Cycloeucalenol [7] H3C CH3 H H HO CH3 O HO CH3 CH3 O O (CH 2)14 H3C H H3C CH3 O H (43) oleanol 28-aldehyde 3-Opalmitate [54] OH (42) Daucosterol [53] (41) Cycloeucalenol acetate CH3 H3C CH3 H3C O O CH3 CH3 CH3 H H CH3 CH3 HO HO H3C H3C CH3 CH3 (45) Oleanoic acid [54] (44) Ursolic [54] Fig. 4. Structures of the terpenoids isolated from Lobelia sp. H3C H3C CH3 CH3 O O OH O OH O OH O OH O OH OH OH OH HO HO (46) Lobetyolin [6,25,55,56] (47) Lobetyolinin [7,25,56] H3C H3C CH3 H CH3 H H H O O CH3 CH3 H3C HO CH3 CH3 CH3 O CH3 O O CH3 –Amyrin palmitate [7,41,54] H3C H3C H3C CH3 CH3 CH3 O (39) CH3 CH3 CH3 H H (36) H H CH3 H H CH3 H3C CH3 OH OH OH OH OH OH (48) Isolobetyol [35] (49) Lobetyol [35,56] Fig. 5. Structures of the polyacetylens isolated from Lobelia sp. 27 Fitoterapia 134 (2019) 23–38 D.G. Folquitto et al. O elucidation of three new alkaloids, namely, cis-8,10-diethy 1–3,4-dehydrolobelidiol, (15), trans-8-ethyl-10-phenyl-3,4-dehydrolobelidiol, (16), and cis-8-ethyl-10-phenyl-3,4-dehydrolobelidiol (17). These alkaloids were also identified in the same species in Egypt [50,51]. Alkaloid exhibiting glycosidase-inhibiting activity were isolated from the methanolic extract of L. sessilifolia, 7-O- β –D-glucopyranosylhomonojirimycin (18). Radicamine A (19) and radicamine B (20) are pyrrolidine alkaloids isolated from L. chinensis. 7-O- β –D-glucopyranosyl-homonojirimycin (18) has been reported as a potent α-glycosidase inhibitor of rice glycosidase and all types of mammalian α-glycosidases and as an oral antidiabetic agent. [33,46,52]. Kesting et al. [6] identified two new alkaloids from the crude extract of the aerial parts of L. siphilitica namely, (2R,6S,2′′S), [2′′-O-Acetyl lobeline] (25) and 6-[(E)-2-(3-Methoxyphenyl) ethenyl]-2,3,4,5-tetrahydropyridine (26). The lobeline is cited in the literature, in most of the species of genus Lobelia, as an alkaloid with important biologically activities and has been subject of several important pharmacological studies, for presenting medicinal properties as respiratory stimulant, helping neurological disorders and treatment of drug abuse [5]. However, in present study, due to the inclusion criteria established, were only considered articles that relate the isolation of the chemical compound of a given species and/or where the chemical compound or fraction was biologically tested and not commercially acquired. This condition led us to have no articles for the discussion about lobeline. CH3 O HO O H3C OH OH HO (50) 7,8-erythro- and 7,8-threotrihydroxy- -dimethoxy- -neolignas [35] Fig. 6. Structures of the neolignan isolated from Lobelia sp. (1.35%). Their structures are presented in Figs. 1–10, which presents the isolation of 80 compounds. We emphasize that the best known species is the American L. inflata and can be traced over many centuries and contains the greatest concentration of > 20 piperidine alkaloids [5]. Along the years the interest in this class of molecules has increased and new researches over other species were being performed. In the last few years the most studied species was L. chinensis which has demonstrated important biological properties as antitumoral actvity [11]. 3.2.1. Alkaloids For years, it has been shown that Lobelia (Campanulaceae) species are characterized by the large presence of alkaloids containing a piperidine or N-methylpiperidine ring and one or two substituents at the C2 and/or C6 position of the ring (Fig. 2). Piperidine alkaloids are an extensive family of compounds of great interest, because they have important biological activities [5]. The phytochemical investigation of this genus in the present study collected 35 alkaloids shown in Fig. 3. Charlier and Tounder [59] and Steinegger and Egger [38] extracted the alkaloid fraction of L. giberroa Hemsl. The alkaloids lophilacrin (1) and lophilin (2) were isolated from the alkaloid fraction of L. siphilitica [67, 68]. Gedeon and Gedeon [39] isolated and identified lobelanidine (3) (major alkaloid) and lelobanidine (4) in L. nicotianaefolia from a chloroform (CHCl3) fraction. From the aerial parts of L. tupa and L. inflata, the following alkaloids were identified: lobeline (6), lobelanine (5), lobelanidine (3), norlobelanidine (7), norlobelanine (8), norlobeline (21), 8-propyl-10-phenyl lobelionol (28), 3-hydroxy-3-phenyl-propanoic norallosedamine (22), and 3-hydroxy-3-phenyl-propanoic allosedamine (23). Among them, lobeline (6) appears to be the one with the highest yield and is most commonly found in the species L. urens, L. portoricensis, L. inflata, L. nicotianaefolia, and L. siphilitica [6,13,26,29,40,42–44]. Lobinaline (9) was obtained by acid-base extraction of the CHCl3 fraction of the methanolic extract from the aerial parts of L. cardinalis [32]. This was the first binitrogenous alkaloid discovered and later found in other species of Lobelia [40,47,48,49]. The following three piperidine alkaloids were isolated from the total alkaloid extract of L. berlandieri, a Mexican toxic species: [N-methyl-2,6bis(2-hydroxybutyl)-∆3-piperidine] (11), [N-methyl-2- (2-hydroxypropyl)-6-(2-hydroxybutyl)-∆3-piperidine] (12), [N-methyl-2-(2-oxobutyl)-6–(2-hydroxybutyl) ∆3-piperidine] (13) [10]. In 2014, Yang et al. [35] isolated and identified these three alkaloids from L. chinensis, and four other alkaloids, namely, lobechidine A (32), lobechidine B, (33), lobechidine C (34), and andrachcinidine (35). Lelobanonoline (14) was first identified in L. davidii, a Chinese species, by Zhang, Wang and Zhou [41]. It was also isolated from young stems of L. polyphylla Hook & Arn in Chile by Villegas et al. [29], along with the following piperidine alkaloids: 1-(1-(2-hydroxy-2-phenylethyl)-1-methylpiperidin) butane-2-ol (27); 8-propyl-10-phenyl lobelionol, (28); 1-(6-(2-hidroxypentyl)-1-methylpiperidin) butane-2-one (29); and 1-methyl-2-piperidinemethanol (30). Phytochemical investigation of leaves, stems, and flowers of L. laxiflora in Costa Rica resulted in the isolation and structural 3.2.2. Terpenoids Terpenoids are a class of secondary metabolites commonly found in plant species, derivative of isopentenyl pyrophosphate and are ubiquitously distributed throughout the plant kingdom being able to be in the form of free triterpenoids, triterpenic glycosides (saponins), phytosterols and/or their precursors [70]. There is constant interest in these metabolites for presenting in the antitumor activities and their potential for treatment or prevention of diabetes and Alzheimer's disease [71]. In the genus Lobelia, the following terpenoids were isolated and identified from the hexane fraction of the species L. davidii: β–amyrin (38), β-sitosterol (36); β-amyrin palmitate (39) [41]; L. chinensis: daucosterol (42) [53], stigmasterol (37); cycloeucalenol (40); cycloeucalenol acetate [7]. Sun et al. [54] isolated and identified triterpenoids β-sitosterol (36); ursolic acid (44), oleanoic acid (45) and one novel triterpenoid ester, oleanol 28-aldehyde 3-O- β -palmitate (43) from the aerial part of L. sessilifolia. The chemical structures of the flavonoids present in the Lobelia genus are represented in Fig. 4. 3.2.3. Polyacetylens About seven hundred polyacetylenes have been isolated mainly from plants belonging to the family of Asteraceae, Umbelliferae and Campanulaceae [72]. The family Campanulaceae have demonstrated the presence of C14-polyacetylene derivatives, and therefore, they have been investigated as potential chemosystematic markers [55,57,60]. Four polyacetylenes were reported from the L. chinensis: lobetyolin (46); lobetyolinin (47); isolobetyol (48); and lobetyol (49) [35]. Ishimaru, Yonemitsu and Shimomura (1991) [55] isolated two novel compounds of polyacetylene lobetyolin (9-O-β-D-glucopyranosyl2,10-tetradecadien-4,6-diand-8,14-diol) (46) and lobetilol (49) (2,10tetradecadien-4,6-diyne-8,9,14 triol) from L. inflata hairy roots, and their structures were established based on chemical and spectroscopic evidence [56]. Polyacetylenes lobetyolin (46) and lobetyolinin (47) were also present in L. inflata hairy roots culture identified and quantified by HPLC [25] and in the methanol extract of the whole plant L. chinensis. Lobetyolin was isolated from the root extract L. siphilitica [6]. The Fig. 5 shows structures of the polyacetylens isolated from Lobelia sp. 3.2.4. Neolignans Lignoids are abundant in plants rich in fibers, and their skeleton is 28 Fitoterapia 134 (2019) 23–38 D.G. Folquitto et al. HO OH + O HO O OH OH OH HO OH O OH OH HO O OH O O O O O O O OH O HO HO OH HO O HO OH HO HO O HO OH OH HO O O O O HO CH3 O O O OH HO O CH3 O OH OH O CH3 OH HO O OH OH CH3 HO OH OH (52) Rutin [57] OH O (53) Hesperidin [53,57] (51) Apigenin 7-O-rutinoside [56] OH O O CH3 HO O OH OH OH HO HO HO O O OH (55) Amentoflavone [57] Fig. 7. Structures of the flavonoids isolated from Lobelia sp. 29 O OH O (54) Hesperetin [57] OH O OH O (56), Apigenin [36,53,57] Fitoterapia 134 (2019) 23–38 D.G. Folquitto et al. OGlic -- Caf OH + HO O OGlic OH O CH3 O H OGlic --Malony l (72) Lobelinin A [79] OGlic -- Caf OH + HO O OGlic OGlic --Rha --Coum OH O O CH3 O OGlic --Malony l (73) Lobelinin B [79] Fig. 7. (continued) H3C Fig. 8. Structures of the coumarins isolated from Lobelia sp. O H HO O H3C H3C H3C O O O (74) Scoparone [7,54,57] H3C O O O O O OH O (76) 5,7-dimethoxy-8hydroxycoumarin [53,54] (75) Isoscopoletin [57] formed by a basic units of phenylpropane group (C6-C3)n. In our research, two neolignans, 7,8-erythro- and 7,8-threo-4,9,9′- trihydroxy3,3′-dimethoxy-8.O.4′-neolignans, were reported in L. chinensis by Yang et al. [35] (Fig. 6). Neolignans are a large group of naturally occurring phenols which are widely distributed within in plants, are derived from the shikimic acid biosynthetic pathway, and their skeleton is formed by a basic units of phenylpropane group (C6-C3)n. [73]. 3.2.5. Flavonoids Flavonoids are a group of natural substances with variable phenolic structures and are widely distributed in the plant kingdom and commonly found in fruits, vegetables and certain beverages. Flavonoids are considered an indispensable component in nutraceutical, pharmaceutical, medicinal and cosmetic applications because they have antioxidant, anti-inflammatory, anti-mutagenic and anti-cancer properties along with their ability to modulate key cellular enzyme function. 30 Fitoterapia 134 (2019) 23–38 D.G. Folquitto et al. O H N H antiinflammatory, insecticidal, antifungal, and antitumor properties. They are also involved as an intermediate product in the synthesis of therapeutic agents. When amides are conjugates with other aliphatic, aromatic and heterocyclic ring produces various type of biological activity. Generally, benzylamides were found to be more active than other amides [76]. In the Lobelia genus aurantiamide acetate (77) was isolated of L. chinensis. (Fig. 9). The Fatty Acids and Acids isolated and identified in Lobelia genus were found in study on the chemical constituents L. chinensis: (78) Palmitic acid [53], (79) Lacceroic acid [53], (80) Stearic acid [53] (Fig. 10). O H N O O H CH3 (77) Aurantiamide acetate [7] Fig. 9. Structures of the amide isolated from Lobelia sp. 3.3. Pharmacological effects of lobelia extracts and isolated compounds Several species of Lobelia presenting biological activities such as antimicrobial, anti-inflammatory, cytotoxic, and neuroprotective effects have been studied. All pharmacological activities reported in various publications included the present study are shown in Table 1. Numerous preclinical studies and some clinical studies suggest that flavonoids have the potential to reduce the risk of cancer and cardiovascular disease [36]. In the Lobelia genus the flavonoids were mentioned in L. chinensis and L. erinus. In L. chinensis, the following flavonoids were isolated and identified (Fig. 7): apigenin 7-O-rutinoside (51); rutin (52); hesperidin (53); hesperetin (54); amentoflavone (55); apigenin (56); naringenin (57); luteolin, (58); chrysoeriol (59); eupafolin (60); diosmetin (61); quercetin (62); quercetin 3-O-α-L-rhaminoside (63); quercetin 3-O-βD-glucoside (64); quercetin 7-O-α-L-rhaminoside (65); linarin (66); diosmin (67); apigenin-7-O-[β-D-glucuronopyranosyl (1 → 2) O- βglucuronopiranoside (68); and chrysoeriol-7-O-[β-D-glucuronopyranosyl (1 → 2) O- β-glucuronopiranoside (69) [7,36,53,56,57]. Lobelia erinus is an ornamental species, rich in anthocyanidins that were identified by Yoshitama (1977) [78] as Delphinidin 3,5,3′-triglucoside (70) and Delphinidin 3-rutinoside-5,3′-glucoside (71) and by Kondo (1989) [79], such as Lobelinin A (72) e Lobelinin B (73). 3.3.1. Respiratory stimulation Meléndez et al. (1967), in Spain, tested the action of lobeline and norlobelanine, from extract Lobelia portoricensis, in animals and found that they inhibited bronchospasms in the various animals tested (Table 2) and for a long time lobeline, obtained from L. inflata, remained the most important drug for the treatment of respiratory problems [5]. 3.3.2. Anti-inflammatory activity Some species of Lobelia genus has been traditionally used in the treatment of inflammation. Research on the species L. laxiflora, L. chinensis, L. flaccida and L. nicotianaefolia were developed in order to verify how this effect occurs (Table 3). The anti-inflammatory properties of L. laxiflora were evaluated in in vivo models of rat paw edema [carrageenan (Car)-induced and cobra venom (CV)-induced models] and in vitro models by the activation of complement system units by alternative pathway (AP) and classical pathway (CP). Ethanolic extracts of flowers, stems, and leaves, non-alkaloid fraction, alkaloid fraction, and the three alkaloids isolated (15), (16) and (17) were tested. A strong suppression of edema in both the models, mainly by the ethanolic extract of the flower when compared to standards (acetylsalicylic acid and indomethacin) was observed. The crude extracts and non-alkaloid fractions selectively inhibited CP activity, while the alkaloid fraction and (16) were active in both AP and CP assays. The alkaloids (15) and (17) were moderately active, but their inhibitory effect was selective and directed to CP activity. The results of the application of extracts and alkaloids in the two models of edema revealed their action in vivo. Since the complement system underlies the inflammatory reactions, the inhibition of complement activity is expected to prevent the development of the inflammatory response [50]. Kuo et al. [7] characterized 46 compounds of the CHCl3, n-butanol, 3.2.6. Coumarins Coumarins are a group of secondary metabolites that show characteristic odor and taste like vanilla. They belong to the phenolic substances group made of fused benzene and α-pyrone rings [74]. In plants, coumarins contribute to the defense against phytopathogens, response to abiotic stresses, regulation of oxidative stress, and probably as signaling molecules. They have a antimicrobial properties for example, the coumarin, scopoletin was isolated as antitubercular constituents of the whole plant Fatoua pilosa [75]. In the genus Lobelia, three coumarins, namely, scoparone (74), isoscopoletin (75), and 5,7-dymethoxy-8-hydroxycoumarin (76) were isolated from L. chinensis. [7,53,54,57] and are represented in the Fig. 8. 3.2.7. Other chemical compounds such as amides, fatty acids and acids Amides were associated with wide spectrum of biological activities including antituberculosis, anticonvulsant, analgesic, HO O CH3 OH O CH3 (78) Palmitic acid [53] (79) Lacceroic acid [53] HO CH3 O (80) Stearic acid [53] Fig. 10. Structures of the fatty acids isolated from Lobelia sp. 31 Fitoterapia 134 (2019) 23–38 D.G. Folquitto et al. Table 2 Respiratory stimulation activity of Lobelia species. Lobelia species Extracts/compounds Active concentration Model used Effects References Lobelia portoricensis Urban Lobeline Norlobelanine 12–30 μg Respiratory stimulation in animals Respiratory stimulation in dogs; mild effect in lowering blood pressure of dogs; inhibition of ACTH action on intestinal isolates in rabbits and guinea pigs [43] aeruginosa, Candida albicans, Aspergillus niger [27], and Salmonella typhi [61]. Methanolic, ethyl acetate, CHCl3, petroleum ether, and aqueous extracts were prepared using leaves and roots. The CHCl3 extract of the leaves showed strong activity against S. aureus (17.5 mm) and P. aeruginosa (23.33 mm), which was equal to and greater than the Streptomycin standard tested, respectively [27]. This finding is in agreement with the results of the study by Kalaimathi et al. [61], who showed a strong antimicrobial activity for CHCl3 and methanolic extracts against S. aureus, P. aeruginosa, S. typhi, and E. coli when compared to the standard antibiotics ciprofloxacin, cefotaxime, and amoxycillin. The ethanolic extract of L. chinensis was tested along with 57 other traditional Chinese plants to verify its antifungal and antibacterial potential against A. fumigatus, C. albicans, Acinetobacter baumannii, P. aeruginosa, and S. aureus. L. chinensis showed inhibitory activity against A. fumigatus [34]. The n-hexane fraction of L. chinensis showed a strong inhibitory activity against Mycobacterium tuberculosis, suggesting that this species could be used as a potential anti-M. tuberculosis agent by consistently inhibiting or blocking tuberculosis [62]. and aqueous extract of L. chinensis. Screening for anti-inflammatory and antiviral activity was performed by inhibition of HSV-1 replication, superoxide anion generation, and elastase release bioactivity. The CHCl3 extract and the compounds (31), (39), (61), (73) did not show an antiviral activity against HSV-1; however, the CHCl3 fraction and (70) inhibited superoxide generation. In addition, the CHCl3 fraction showed a significant inhibition of elastase release and (31) showed a moderate inhibition. In another study on L. chinensis, the possible mechanisms underlying the anti-inflammatory activity of the methanolic extract and fractions of L. chinensis were investigated by determining the suppression of NO production induced by LPS in RAW264.7 macrophages and by using the model of rat pulmonary traumatism. The results showed that the methanolic extract and its fractions in the concentration range of 62.5–250 g/mL did not induce cytotoxicity. The ethyl acetate fraction showed better inhibition of NO production than other fractions. In contrast, rats pretreated with the ethyl acetate fraction (62.5, 125, and 250 mg/kg) showed a decrease in proinflammatory cytokine levels (TNF-α, IL-β, and IL-6) and inhibition of expression of iNOS and COX-2 through the NF-kB pathway. These results suggested that L. chinensis had an anti-inflammatory effect via the NF-kB pathway [36]. The aqueous extract of L. flaccida was analyzed for its anti-inflammatory activity by induction of rat paw edema with carrageenan. The LD50 of the aqueous extract was ≥5000 mg/kg orally, indicating significant anti-inflammatory activity in rat paw edema [31]. 3.3.4. Anticonvulsant/neuroprotective activity Secondary metabolites of the species of the genus Lobelia have presented therapeutic potential for various neurological disorders. L. nicotianaefolia has been traditionally used in India as an antiepileptic. Tamboli et al. [13] verified the antiepileptic action of lobeline (6) (the major alkaloid of L. nicotianaefolia) and its effects on GABA level in rat brain in seizures induced by PTZ. They concluded that (6) showed potent anticonvulsant activity with a significant increase in GABA level in the brain and consequent reduction of epileptic seizures. The aqueous extract of L. flaccida, which is used against epilepsy in Africa, had a weak anticonvulsant action in PTZ-induced seizures [31]. Alzheimer's disease is a progressive, degenerative, neurological disease that results in impaired memory and behavior. The use of acetylcholinesterase inhibitors (AChE) is one of the treatment strategies for Alzheimer's disease. Yang et al. [63] performed a screening with 31 plant species to verify the action of alkaloid fraction on AChE inhibitory activity for the treatment of Alzheimer's disease. L. chinensis showed low AChE inhibitory activity. However, Rahman and Monem [51] tested the alkaloid fraction of L. laxiflora roots and observed a potent inhibition of AChE when compared to the standard eserine (286.3 and 270 μg/mL respectively). L. cardinalis was screened from a library of extracts of 1000 plant species native to the Southeastern United States, and nicotinic acetylcholine receptor (nicAchR), which is relatively nonselective for the α4β2 and α7-nicAchR subtypes, was identified in L. cardinalis. This binding profile of nicAchR is atypical of plant-derived nicAchR ligands, most of which are highly selective for α4β2-nicAchRs, and it has a therapeutic relevance, because the agonism of α4β2 and α7 icAchRs is associated with anti-inflammatory and neuroprotective properties. Lobinaline (9) was identified as the major compound of L. cardinalis. It was proved to be a potent free radical scavenger, has similar binding affinity for α4β2 and α7-nicAchRs, exhibited agonist activity on nicAchRs in SH-SY5Y cells, and inhibited absorption of [3H]-dopamine (DA) in rat striatal synaptosomes. These multifunctional effects make lobinaline (9) a compound of interest for the development of therapy for neuropathological disorders involving free radical generation, cholinergic and dopaminergic neurotransmission including 3.3.3. Antimicrobial activity Studies of antimicrobial activity of Lobelia species were carried out mostly with extracts or fractions of methanolic, ethanolic, chloroform, hexane and essential oil. No antimicrobial tests were observed with isolated compounds, however the studies presented below show an excellent antimicrobial potential for some species. Results for antimicrobial activity are summarized in Table 4. The essential oil of L. pyramidalis showed moderate antimicrobial activity in disc diffusion method, and the minimum inhibitory concentration method against Trichophyton mentagrophytes (MIC = 3.12 mg/mL), Pseudomonas aeruginosa, Escherichia coli, and Aspergillus fumigatus (12.50 mg/mL) were determined. The authors report that the antimicrobial activity may be related to the presence of terpenes in the essential oil, which had perilla ketone and isophytol as the major compounds [30]. L. inflata is a plant popularly used for respiratory problems such as asthma and bronchitis. Therefore, the antimicrobial activity of this species was mainly determined against respiratory tract pathogens. The maximum inhibitory activity was observed for methanolic and ethanolic extracts of inflorescence against Klebsiella pneumonia and Staphylococcus aureus, respectively. The ethanolic and methanolic extracts of inflorescence presented minimal inhibitory effects against Serratia marcescens, K. pneumonia, and S. aureus. Among all the stem extracts, the ethanolic extract was more effective against S. marcescens. The ethanolic extract of the root was active against S. marcescens and S. aureus. The methanolic extract of the callus inhibited the growth of Cryptococcus neoformans among the various pathogenic fungi [4]. L. nicotianifolia is popularly used in dressing of wounds, burns, boils, cuts, and in other antibacterial preparations. Its antimicrobial activity was studied against K. pneumoniae, S. aureus, Proteus vulgaris, P. 32 D.G. Folquitto et al. Table 3 Anti-inflammatory activities of Lobelia species. Lobelia species Extracts/compounds Active concentration Model used Effects References Lobelia laxiflora L. Ethanolic extract of stem and flower, alkaloid fraction, and alkaloids (15), (16) and (17) Alkaloid fraction and alkaloids (16) and (17) Chloroform extract 100 mg/kg In vivo: Induction of rat paw edema by Carrageenan (Car) and cobra venom (CV) Strong Car-induced suppression of paw edema and moderate CVinduced suppression [50] 0.125 to 1.0 mg/mL In vitro: in normal human serum (NHS) by microtiter test In vivo Induction of inflammation by acetic acidinduced writhing method Strong inhibitory activity of the complement system (40 to 90%) by the classical pathway 28.82 and 48.48% reduction of writhing Lobelia nicotianaefolia 33 Ethanolic extract Chloroform extract and ethanolic extract Lobelia chinensis Lobelia flaccida Lobelia chinensis Ethanolic extract Methanolic extract and fractions Ethyl acetate fraction 100 and 200 mg/kg 100 and 200 mg/kg Induction of inflammation by the method of writhing induced by hot plate 62.5–250 g/mL In vitro cytotoxicity Suppression of the production of nitric oxide induced by LPS in RAW264.7 macrophages In vivo Model of acute lung injury in rat Ethyl acetate fraction Pretreatment of rats (62.5, 125, and 250 mg/kg) Aqueous extract Chloroform fraction Compound (70) Chloroform fraction LD50 ≥ 5000 mg/kg orally 4.75 μg/mL IC50 = 6.7 μM IC50 = 2.45 μg/mL Compound (31) IC50 = 25 μM Rat paw edema induced by carrageenan Superoxide anion generation Inhibition of elastase release by neutrophil degranulation [28] 61.73 and 62.60% reduction of writhing Significant increase in mean latency time compared to control Potential neutralization of PLA2 fraction of cobra venom Did not induce cytotoxicity Showed better inhibition activity of nitric oxide than other fractions Decrease in proinflammatory cytokines (TNF-α, IL-β, and IL-6) and inhibition of iNOS and COX-2 expression via the NF-kB pathway. Significant anti-inflammatory action Significant inhibition of superoxide anion (70) exhibited significant inhibition of superoxide anion Significant inhibition of superoxide anion [36] [31] [7] Moderate inhibition of superoxide anion Fitoterapia 134 (2019) 23–38 D.G. Folquitto et al. Table 4 Antimicrobial activities of Lobelia species. Lobelia species Extracts/compounds Lobelia chinensis Chloroform, n- butanol, aqueous fraction, and compounds, (31), (39), (61), (73) Essential oil Lobelia pyramidalis Lobelia nicotianaefola Chloroform extract of leaves Ketone extract of leaves Chloroform extract of the root Lobelia inflata Active concentration Inhibition zone of 15.16 mm Inhibition zone of 18.3 mm Inhibition 23.33 mm Inhibition 17.5 mm Model used Effects References In vitro Inhibition of HSV-1 replication There was no antiviral effect [7] In vitro Using the disc diffusion method and microdilution technique Moderate level of antimicrobial activity. Trichophyton. mentagrophytes (MIC = 3.12 mg/mL), Pseudomonas. aeruginosa, Escherichia. coli, and Aspergillus. fumigatus (12–50 mg/mL) Weak to moderate Inhibitory effect against Staphylococcus. aureus and T. mentagrophytes Antimicrobial activity against strains: S. aureus [30] In vitro Agar-well Diffusion In vitro Agar disc diffusion Antimicrobial activity against strains: S. aureus 34 Methanolic and ethanolic extract of inflorescence In vitro Disc diffusion method Ethanolic extract of stems In vitro Disc diffusion method In vitro Disc diffusion method In vitro Microdilution on plates In vitro Disc diffusion method for Streptococcus pyogenes, P. aeruginosa, S. aureus, Klebsiella terrigena, Bacillus subtilis, E. coli, C. albicans Cryptococcus neoformans, Trichosporon Ethanolic extract of roots Lobelia chinensis Alcohol extract Lobelia nicotianaefolia Ethanolic extract 0.1 mg/mL Chloroform extract Lobelia nicotianaefolia Methanol extract Chloroform extract n-hexane extract 400–800 μg/mL In vitro Agar-well diffusion In vitro Agar-well Diffusion In vitro resazurin microtiter assay (REMA) using a 96-well micro-plate and mycobacteria growth indicator tube (MGIT) 960 system assay Antimicrobial activity against strains P. aeruginosa Antimicrobial activity against strains S. aureus Antimicrobial activity Maximum inhibition against Klebsiella. pneumoniae and S. aureus Minimum inhibition against S. aureus, Serratia marcescens, K. pneumonia Antimicrobial activity Maximum inhibition against S. marcescens Antimicrobial activity Maximum inhibition against S. marcescens and S. aureus High inhibitory activity against A. fumigatus Good inhibitory activity against Streptococcus pyogenes (32 mm), high for E. coli (33 mm) High inhibition Cryptococcus neoformans (33 mm) and P. aeruginosa (28 mm) Strong antibacterial activity against S. aureus and P. aeruginosa [4] [34] [28] [61] Strong antibacterial activity against Salmonella typhi and E. coli Strong inhibitory activity on the growth of Mycobacterium tuberculosis [62] Fitoterapia 134 (2019) 23–38 Lobelia chinensis [27] Lobelia species Extracts/compounds Active concentration Model used Effects References Lobelia nicotianaefolia Lobelia chinensis Compound (6) Alkaloid fraction 20 mg/kg 18.5% Potent anticonvulsant activity upon PTZ induction Low acetylcholinesterase inhibitory activity for the treatment of Alzheimer's Disease [13] [63] Lobelia laxiflora Alkaloid fraction 286 μg/mL PTZ-induced convulsion model Ellman's method modified by bioautography Spectrophotometric method [51] Lobelia cardinalis Compound (9) potent cholinesterase inhibiting activity comparing to serine, according to a slightly modified spectrophotometric method Showed neuroprotective effect by similar binding affinity on α4β2 and α7-nicAchRs, exhibited agonist activity on nicAchRs in SH-SY5Y cells, and inhibited [3H] -dopamine (DA) uptake in rat striatal synaptosomes D.G. Folquitto et al. Table 5 Anticonvulsant/neuroprotective activities of Lobelia species. [32] 35 Table 6 Antitumor activities of Lobelia species. Lobelia species Extracts/compounds Active concentration Model used Effects References Lobelia chinensis Aqueous extract Aberrant crypt foci (ACF) model Showed low, medium, and high inhibition in precancerous lesions in rats respectively (dose-dependent) [64] Lobelia chinensis (11), (12), (13), (32), (33), (34), (35), (48), (49), and (50) Dose/inhibition rate 0.15 g/kg/ 8.12%; 0.45 g/kg/59.42%; and 1.35 g/kg/65.44% IC50 between 9.31 and 12.36 μM 5-diphenyl-2H-tetrazolium bromide (MTT) assay in (MSTO211H) and (NCI-H292) lung cancer cell lines Moderate cytotoxic activity against both types of lung cancer cell lines (48) IC50 = 12.36 and 9.31 μM (49) IC50 = 11.76 and 9.64 μM Other compounds showed no activity [34] Fitoterapia 134 (2019) 23–38 Fitoterapia 134 (2019) 23–38 [37] Increased cell proliferation, phagocytosis, production of nitric oxide, and secretion of cytokines in a dose-dependent manner. Inhibitory activity on glycosidases. Presented significant inhibitory potential for porcine kidney α trehalase MTT assay of nitric oxide release; effect of Toll-like receptor 4 (TLR4) inhibitor by ELISA; Phagocytosis assay with RAW 264.7 macrophages In vitro Enzymatic and colorimetric methods neurodegenerative conditions such as Parkinson's disease, and drug abuse [32]. A Table 5 shows anticonvulsant and neuroprotective activities of Lobelia genus. [52] References Effects Model used 3.3.5. Antitumor activity Medicinal plants have been a rich source of compounds of value to medicine. More than half of currently available drugs are natural compounds used to treat cancer that have been isolated from natural products. There are reports of over 3000 plants worldwide that have anticancer properties. The search for improved cytotoxic agents continues to be an important line in the discovery of modern anticancer drugs [58, 77].In the Lobelia genus, investigations with the aqueous extract of L. chinensis were performed on precancerous colon lesions of rats induced by dimethylhydrazine (DMH) using the aberrant crypt foci (ACF) model, it was observed that the number of apoptotic cells from rats in the DMH group did not differ significantly from that in the control group, while the difference was obvious between the control group and the group treated with L. chinensis. The rates of inhibition of low, medium, and high doses were 8.12, 59.42, and 65.44%, respectively. Medium and high doses may significantly inhibit ACF formation [64]. Compounds isolated from the ethanolic extract of L. chinensis, (11), (12), (13), (32), (33), (34), (35), (48), (49) and (50), were tested to determine cytotoxic activity against MSTO-211H and NCI-H292 lung cancer cell lines. Only polyacetylenes (48) and (49) exhibited moderate cytotoxic activity against the two cell lines [35]. Several other alkaloids such as camptothecin (CPT), a known topoisomerase I (TopI) inhibitor [65], and vinblastine, which interacts with tubulin, have been successfully developed into chemotherapeutic drugs [66]. A Table 6 shows antitumor activities de Lobelia genus. 3.3.6. Immunomodulating activity and inhibitors of α-glycosidases Inhibitors of α-glycosidases are polysaccharides that exist in large amounts in L. chinensis and can reach 25% by weight of the dried herb. Plant polysaccharides have shown biological activities such as the ability to modulate immune function. A neutral α-glucan (BP1) was isolated from a hot water extract of L. chinensis and the assays performed showed that BP1 was able to increase cell proliferation, phagocytosis, NO production, and cytokine secretion in a dose-dependent manner (Table 6) [37]. Some species of the Campanulaceae family have demonstrated potent inhibitory action against α-glycosidases. Ikeda et al. [52] tested the alkaloid (18) isolated from the 50% methanolic fraction of L. sessilifolia and verified its potent inhibitory activity on porcine kidney trehalase enzyme. Two new pyrrolidine alkaloids, radicamine A (19) and radicamine B (20), were isolated from L. chinensis, and exhibited inhibitory activity on α-glycosidases, confirming that polyhydroxy alkaloids with aromatic ring may demonstrate activities similar to the previously known 1-deoxynojirimycin (Table 7) [33]. α-glucan-BP1, Compound (18) Lobelia chinensis Lobelia sessifolia IC50 = 1.7 μM Active concentration Extracts/compounds Lobelia species Table 7 Immunomodulating activity and inhibitors of α-glycosidases activities of Lobelia species. D.G. Folquitto et al. 3.3.7. Analgesic activity and antivenom activity against cobra venom L. nicotianaefolia leaves are popularly used in India to treat various diseases, including pain and snakebites. Vigneshwaran et al. (2014) tested the analgesic, antivenom, and antimicrobial activity of CHCl3, ethanolic, and aqueous extracts of this species. Among the three extracts, the ethanolic fraction showed significant antimicrobial, analgesic, and antivenom properties, whereas the activity was moderate in the CHCl3 fraction and low in the aqueous fraction. Taken together, this study justifies the strong pharmacological properties of L. nicotianaefolia. 4. Limitations of the review There are certain limitations to this review. Although a systematic approach was applied to the research, selection, and analysis of the 36 Fitoterapia 134 (2019) 23–38 D.G. Folquitto et al. retrieved studies, it was not possible to conduct meta-analyses due to the small number of studies on the subject that was exhausted with the fact that each was very different from the other. In addition, the quality of the studies was not assessed due to the lack of an adequate instrument. However, this review allowed us to summarize the research in the particular area and identify important aspects that could be addressed in future research projects. https://doi.org/10.1016/s1875-5364(14)60016-9. [12] G. Zheng, D.B. Horton, N.R. Penthala, J.R. Nickell, J.P. Culver, A.G. Deaciuc, L.P. Dwoskin, P.A. Crooks, Exploring the effect of N-substitution in nor-lobelane on the interaction with VMAT2: discovery of a potential clinical candidate for treatment of methamphetamine abuse, Medchemcomm. 4 (2013) 564–568, https://doi. org/10.1039/C3MD20374C. [13] A.M. Tamboli, R.A. Rub, G. Pinaki, S.L. Bodhankar, Antiepileptic activity of lobeline isolated from the leaf of Lobelia nicotianaefolia and its effect on brain GABA level in mice, Asian Pac. J. Trop. Biomed. 2 (2012) 537–542, https://doi.org/10.1016/ S2221-1691(12)60092-6. [14] W. Ahmed, Z. Ahmad, A. Malik, Stigmasteryl galactoside from Rhynchosia minima, Phytochemistry 31 (1992) 4038–4039. [15] V. Cechinel Filho, Principais avanços e perpectivas na área de produtos naturais ativos: estudos desenvolvidos no NIQFAR, Quim Nova 23 (2000), https://doi.org/ 10.1590/S0100-40422000000500017. [16] S. Virtuoso, A. Davet, J.F.G. Dias, M.M. Cunico, M.D. Miguel, A.B. Oliveira, O.G. Miguel, Estudo preliminar da atividade antibacteriana das cascas de Erythrina velutina Willd., Fabaceae (Leguminosae), Rev. Bras. Farm 15 (2005) 137–142, https://doi.org/10.1590/S0102-695X2005000200012. [17] D.A. Costa, D.A. Costa, M.H. Chaves, W.C.S. SILVA, C.L.S. Costa, Constituintes químicos, fenóis totais e atividade antioxidante de Sterculia striata St. Hil. et Naudin, Acta Amaz 40 (2010) 207–212, https://doi.org/10.1590/S004459672010000100026. [18] S. Parvin, Md.A. Kader, Md.A. Muhit, Md.E. Haque, Md.A. Mosaddik, Mir I.I. Wahed, Triterpenoids and phytosteroids from stem bark of Crataeva nurvala buch ham, J. Appl. Pharm. Sci. 1 (2011) 47–50, https://doi.org/10.1590/S010040422012000300016. [19] S.B. Patil, A.P. Rajput, Chemical constituents from petroleum ether extract of leaves of Butea monosperma and their antimicrobial, antifungal activity, Int. J. Pharmtech. Res. 4 (2012) 321–326. [20] A. Sen, P. Dhavan, K.K. Shukla, S. Singh, G. Tejovathi, Analysis of IR, NMR and antimicrobial activity of β-sitosterol isolated from Momordica charantia, Sci. Secur. J. Biotech. 1 (2012) 9–13. [21] G. Testa, P.R.N. Oliveira, C.C. Silva, I.T.A. Schuquel, S.M.O. Santin, Oliveira L.C.M.A. Kato, L.L.M. Arruda, C.A. Bersani-Amado, Constituintes Químicos das folhas e avaliação da atividade antinflamatória das raízes e folhas de Guettarda pohliana MÜLL. ARG. (RUBIACEAE), Quim Nova 35 (2012) 527–529. [22] Y. Ahmed, Y. Ahmed, S. Rahman, P. Akhtar, F. Islam, M. Rahman, Z. Yaakob, Isolation of steroids from n-hexane extract of the leaves of Saurauia roxburghii, IFRJ 20 (2013) 2939–2943. [23] D.G. Folquitto, J.M. Budel, C.B. Pereira, L.E.F. Brojan, G.G. Folquitto, M.D. Miguel, R.Z. Silva, O.G. Miguel, Analytical micrography and preliminary phytochemistry of the leaves and stems of Lobelia exaltata Pohl. (Campanulaceae), Lat. Am. J. Pharm. 33 (2014) 245–250. [24] L.F. Stead, J.R. Hughes, Lobeline for smoking cessation (Review), The Cochrane Library, Published by John Wiley & Sons, Ltd., 2009, p. 3. [25] I. Balvanyos, L. Kursinszki, P. Banyai, E. Szoke, Analysis of polyacetylenes by HPLC in hairy root cultures of Lobelia inflata cultivated in bioreactor, Chromatographia 60 (2004) 235–238, https://doi.org/10.1365/s10337-004-0188-x. [26] L. Kursinszki, K. Ludanyi, E. Szoke, LC-DAD and LC-MS-MS analysis of piperidine alkaloids of Lobelia inflata L. (in vitro and in vivo), Chromatographia 68 (2008) 27–33, https://doi.org/10.1365/s10337-008-0628-0. [27] R.R. Kurdekar, G.R. Hegde, G. Hegde, S.S. Hebbar, Antimicrobial screening of medicinal plants against human pathogens- a comparative account of two different methods of extraction, IJDDR 4 (2012) 82–89. [28] V. Vigneshwaran, M. Somegowda, S. Pramod, Pharmacological evaluation of analgesic and antivenom potential from the leaves of folk medicinal plant Lobelia nicotianaefolia, AJPCT Vol. 2 (2014) 1404–1415. [29] A. Villegas, J. Espinoza, A. Urzua, Piperidine Alkaloids from Lobelia polyphylla Hook. & Arn. (Campanulaceae). B LATINOAM CARIBE PL, Vol. 13 (2014), pp. 205–212. [30] S. Joshi, D. Mishra, G. Bisht, K.S. Khetwal, Essential oil composition and antimicrobial activity of Lobelia pyramidalis Wall, EXCLI J. 10 (2011) 274–279. [31] S. Stolom, I.A. Oyemitan, R. Matewu, O.O. Oyedeji, S.O. Oluwafemi, B.N. NkehChungag, S.P. Songca, A.O. Oyedeji, Chemical and biological studies of Lobelia flaccida (C. Presl) A.DC leaf: a medicinal plant used by traditional healers in Eastern Cape, South Africa, Trop. J. Pharm. Res. 15 (2016) 1715–1721, https://doi.org/10. 4314/tjpr.v15i8.17. [32] D.P. Brown, D.T. Rogers, F. Pomerleau, K.B. Siripurapu, M. Kulshrestha, G.A. Gerhardt, J.M. Littleton, Novel multifunctional pharmacology of lobinaline, the major alkaloid from Lobelia cardinalis, Fitoterapia 111 (2016) 109–123, https:// doi.org/10.1016/j.fitote.2016.04.013. [33] M. Shibano, D. Tsukamoto, A. Masuda, Y. Tanaka, G. Kusano, Two new pyrrolidine alkaloids, radicamines A and B, as inhibitors of alpha-glucosidase from Lobelia chinensis Lour, Chem. Pharm. Bull. 49 (2001) 1362–1365, https://doi.org/10.1248/ cpb.49.1362. [34] L. Zhang, A.S. Ravipati, S.R. Koyyalamudi, S.C. Jeong, N. Reddy, J. Bartlett, P. Smith, M. de la Cruz, M.C. Monteiro, T. Melguizo, E. Jiménez, F. Vicente, Antifungal and anti-bacterial activities of ethanol extracts of selected traditional Chinese medicinal herbs, Asian Pac J Trop Med 6 (2013) 673–681. [35] S. Yang, T. Shen, L. Zhao, C. Li, Y. Zhang, H. Lou, D. Ren, Chemical constituents of Lobelia chinensis, Fitoterapia 93 (2014) 168–174, https://doi.org/10.1016/j.fitote. 2014.01.007. [36] K.C. Li, Y.L. Ho, G.J. Huang, Y.S. Chang, Anti-oxidative and anti-inflammatory effects of Lobelia chinensis in vitro and in vivo, Am. J. Chin. Med. 43 (2015) 269–287, https://doi.org/10.1142/s0192415x15500184. 5. Conclusions This review showed the diversity of species of Lobelia spread across the world with therapeutic potential. The genus Lobelia is an economically important genus of easily cultivable species that represent a large reservoir of chemical compounds. The alkaloid fraction, rich in piperidine alkaloids, the major components of the genus show great promise as therapeutic agents for Central Nervous System (CNS) disorders and antitumoral and anti-inflammatory activities. However, other fractions also revealed important activities such as the hexanic fraction of L. chinensis that presented strong antimicrobial activity against M. tuberculosis. In addition, many other compounds such as flavonoids, terpenoids, and coumarins with therapeutic potential were presented. This study provided the scientific basis for the use of the genus Lobelia L. in future research aimed at the discovery of the chemical compounds responsible for the therapeutic action, as well as the mechanisms involved. Funding This work was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). Declarations of interest None. Acknowledgments The authors would like to thank the Coordenação Aperfeiçoamento de Pessoal de Nível Superior (CAPES). de References [1] E.B.L. Borio, Lobelia langeana Dusén. Contribuição para o estudo farmacognóstico. Tese para concurso à docência livre da cadeira de farmacognosia, da Faculdade de Farmácia da Universidade do Paraná, (1959), p. 86 Brasil. [2] T.G. Lammers, Revision of the infrageneric classification of LOBELIA L. (CAMPANULACEAE: LOBELIOIDEAE), Ann. Mo. Bot. Gard. 98 (2011) 37–62, https://doi.org/10.3417/2007150. [3] R.E. Braga, Lobelias do Brasil. Contribuição para o seu estudo, Tribuna Farmacêutica (1956) 22. [4] G.S. Nagananda, A. Krishnamoorthy, A. Das, S. Bhattacharya, Phytochemical screening and evaluation of antimicrobial activities of in vitro and in vivo grown plant extracts of Lobelia Inflata L, Int. J. Pharm. Bio Sci. 3 (2012) 433–442. [5] F.X. Felpin, J. Lebreton, History, chemistry and biology of alkaloids from Lobelia inflata, Tetrahedron 60 (2004) 10127–10153, https://doi.org/10.1016/j.tet.2004. 08.010. [6] J.R. Kesting, I.L. Tolderlund, A.F. Pedersen, M. Witt, J.W. Jaroszewski, D. Staerk, Piperidine and tetrahydropyridine alkaloids from Lobelia siphilitica and Hippobroma longiflora, J. Nat. Prod. 72 (2009) 312–315, https://doi.org/10.1021/np800743. [7] P.C. Kuo, T.L. Hwang, Y.T. Lin, Y.C. Kuo, Y.L. Leu, Chemical constituents from Lobelia chinensis and their anti-virus and anti-inflammatory bioactivities, Arch. Pharm. Res. 34 (2011) 715–722, https://doi.org/10.1007/s12272-011-0503-7. [8] K. Bone, S. Mills, Herbal approaches to system dysfunctions, Principles and Practice of Phytotherapy, 2nd Ed, Mills, Simon; Churchill Livingstone, Saint Louis, 2013, pp. 183–350 (ISBN 978-0-443-06992-5). [9] W.A. Kukula-Koch, J. Widelski, Chapter 9 – Alkaloids – Badal, Simone, Pharmacognosy, Boston, Academic Press, 978-0-12-802104-0, 2017, pp. 163–198. [10] H.J. Williams, A.C. Ray, H.L. Kim, Δ3-Piperideine alkaloids from the toxic plant Lobelia berlandieri, J. Agric. Food Chem. 35 (1987) 19–22. [11] M.W. Chen, W.R. Chen, J.M. Zhang, X.Y. Long, Y.T. Wang, Lobelia chinensis: chemical constituents and anticancer activity perspective, CJNM 12 (2014) 103–107, 37 Fitoterapia 134 (2019) 23–38 D.G. Folquitto et al. [60] R.K. Bentley, R.H.E. Jones, R.A.M. Ross, V. Thaller, Natural Acetylenes. Part XXXV. Polyacetylenes from the Lobeliaceae Plant Family. A C14 Enediyne Triol from Lobelia cardinalis L, J. Chem. Soc. Perkin Trans. 2 (1973) 140–144. [61] S.K. Kalaimathi, G. Muthu, K. Manjula, Antibacterial activity of Lobelia nicotianifolia against various bacterial strains, Int. J. Life Sci. Pharma Res. 5 (2015) 20–25. [62] W.H. Choi, I.A. Lee, The anti-tubercular activity of Melia azedarach L. and Lobelia chinensis Lour. And their potential as effective anti-Mycobacterium tuberculosis candidate agents, Asian Pac. J. Trop. Biomed. 6 (2016) 830–835, https://doi.org/ 10.1016/j.apjtb.2016.08.007. [63] Z. Yang, D. Zhang, J. Ren, M. Yang, S. Li, Acetylcholinesterase inhibitory activity of the total alkaloid from traditional Chinese herbal medicine for treating Alzheimer's disease, Med. Chem. Res. 21 (2012) 734–738, https://doi.org/10.1007/s00044011-9582-8. [64] S.R. Han, X.Y. Lv, Y.M. Wang, H. Gong, C. Zhang, A.N. Tong, N. Yan, A study on the effect of aqueous extract of Lobelia chinensis on colon precancerous lesions in rats, Afr. J. Tradit. Complement. Altern. Med. 10 (6) (2013) 422–425, https://doi.org/ 10.4314/ajtcam.v10i6.2. [65] M. Huang, H. Gao, Y. Chen, H. Zhu, Y. Cai, X. Zhang, Z. Miao, H. Jiang, J. Zhang, H. Shen, L. Lin, W. Lu, J. Ding, Chimmitecan, a novel 9-substituted camptothecin, with improved anticancer pharmacologic profiles in vitro and in vivo, Clin. Cancer Res. 13 (2007) 1298–1307, https://doi.org/10.1158/1078-0432.CCR-06-1277. [66] W. Li, Y. Shao, L. Hu, X. Zhang, Y. Chen, L. Tong, C. Li, X. Shen, J. Ding, BM6, a new semi-synthetic vinca alkaloid, exhibits its potent in vivo anti-tumor activities via its high binding affinity for tubulin and improved pharmacokinetic profiles, Cancer Biol. Ther. 6 (2007) 787–794. [67] E. Steinegger, F. Egger, Alkaloids of Lobelia siphilitica L, Pharm. Acta Helv. 27 (1952) 113–120. [68] H. Schmidt, E. Steinegger, Knowledge of Lobelia siphilitica alkaloids, Pharm. Acta Helv. 32 (1957) 205–206. [69] D. Moher, A. Liberati, J. Tetzlaff, D.G. Altman, Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement, PLoS Med. 6 (7) (2009), https://doi.org/10.1371/ journal.pmed.1000097. [70] J.M.R. Patlolla, C.V. RAO, Triterpenoids for cancer prevention and treatment: current status and future prospects, Curr. Pharm. Biotechnol. 13 (1) (2012) 147–155, https://doi.org/10.2174/138920112798868719. [71] R.A. Hill, J.D. Connolly, Triterpenoids, Nat. Prod. Rep. 32 (2015) 273–327, https:// doi.org/10.1039/c4np00101j. [72] K.A. El Sayed, Natural products as antiviral agents, Stud. Nat. Prod. Chem. (2000) 473–572, https://doi.org/10.1016/s1572-5995(00)80051-4. [73] R.B. Teponno, S. Kusari, M. Spiteller, Recent advances in research on lignans and neolignans, Nat. Prod. Rep. 33 (9) (2016) 1044–1092, https://doi.org/10.1039/ c6np00021e. [74] J.D.D. Tamokou, A.T. Mbaveng, V. Kuete, Antimicrobial activities of African medicinal spices and vegetables, Medicinal Spices and Vegetables from Africa, 2017, pp. 207–237, , https://doi.org/10.1016/b978-0-12-809286-6.00008-x. [75] R.I. Boysen, M.T.W. Hearn, High performance liquid chromatographic separation methods, Compr. Nat. Prod. II (2010) 5–49, https://doi.org/10.1016/b978008045382-8.00183-0. [76] N. Kushwaha, R.K. Saini, S.K.S. Kushwaha, Synthesis of some Amide derivatives and their biological activity, Int. J. ChemTech Res. (3) (2011) 203–209. [77] M. Gordaliza, Natural products as leads to anticancer drugs, Clin. Transl. Oncol. 9 (12) (2007) 767–776, https://doi.org/10.1007/s12094-007-0138-9. [78] K. Yoshitama, An acylated delphinidin 3-rutinoside-5,3′,5′-triglucoside from Lobelia erinus, Phytochemistry 16 (11) (1977) 1857–1858, https://doi.org/10.1016/00319422(71)85123-3. [79] T. Kondo, J. Yamashiki, K. Kawahori, T. Goto, Structure of lobelinin A and B, novel anthocyanins acylated with three and four different organic acids, respectively, Tetrahedron Lett. 30 (44) (1989) 6055–6058, https://doi.org/10.1016/s00404039(01)93853-5. [37] X.J. Li, W.R. Bao, C.H. Leung, D.L. Ma, G. Zhang, A.P. Lu, S.C. Wang, Q.B. Han, Chemical Structure and Immunomodulating Activities of an alpha-Glucan Purified from Lobelia chinensis Lour, Molecules 21 (2016) E779, https://doi.org/10.3390/ molecules21060779. [38] E. Steinegger, F. Egger, Lophilin and lophilacrin, two new alkaloids from Lobelia, Pharm. Acta Helv. 27 (1952) 207–211. [39] J. Gedeon, S. Gedeon, Alkaloids of Lobelia nicotianaefolia Heyne, Pharm. Acta Helv. 29 (1954) 49–52. [40] F. Kaczmarek, E. Steinegger, Investigations of the alkaloids of Lobelia tupa L, Pharm. Acta Helv. 33 (1958) 257–262. [41] M.Z. Zhang, J.C. Wang, S.H. Zhou, Alkaloids triterpenoids of Lobelia davidii, Phytochemistry 29 (1990) 1353–1354. [42] I.S. Simon, Y.V. Shostenko, Investigation of alkaloids of burning Lobelia, J. Gen. Chem. 32 (1962) 987. [43] E.N. Melendez, L. Carreras, J.R. Gijon, New alkaloid from Lobelia portoricensis urban, J. Pharm. Sci. 56 (1967) 1677–1680, https://doi.org/10.1002/jps. 2600561234. [44] E. Szoke, A. Neszmelyi, I. Balvanyos, A. Krajewska, NMR characterisation of lobeline from Lobelia inflata tissue cultures, Med. Sci. Monit. 4 (1998) 15–19. [45] K. Weinges, W. Bähr, W. Ebert, P. Kloss, Norlobelanidine, the main alkaloid from Lobelia polyphylla Hook and Arn, Justus Liebigs Annalen der Chemie Vol. 756 (1972) 177–180. [46] X.L. Wang, J.M. Sun, Y. Song, H. Zhang, Study on alkaloids in Lobelia sessilifolia by ESI-MSn, Zhongguo Zhongyao Zazhi 33 (2008) 1572–1574. [47] M.G. Chaubal, G.C. Walker, R.M. Baxter, Paper chromatography of alkaloidal extracts of lobelia species, J. Pharm. Sci. 51 (1962) 885–888, https://doi.org/10. 1002/jps.2600510916. [48] D.M. Clugston, D.B. MacLean, R.H.F. Manske, The examination of lobinaline and some degradation products by mass spectrometry, Can. J. Chem. 45 (1967) 39–47. [49] A.S. Goldberg, The Alkaloids of Lobelia yucoide Hillebr, (1966) (Dissertation 99). [50] S. Philipov, R. Istatkova, N. Ivanovska, P. Denkova, K. Tosheva, H. Navas, J. Villegas, Phytochemical study and antiinflammatory properties of Lobelia laxiflora L, Z. Naturforsch. C Bio. Sci. 53 (1998) 311–317. [51] E.H. Rahman, A.R.A. Monem, Cholinesterase inhibiting activity and a new piperidine alkaloid from Lobelia laxiflora L. roots (Campanulaceae) Rec, Nat. Prod. 8 (2014) 199–202. [52] K. Ikeda, M. Takahashi, M. Nishida, M. Miyauchi, H. Kizu, Y. Kameda, M. Arisawa, A.A. Watson, R.J. Nash, G.W. Fleet, N. Asano, Homonojirimycin analogues and their glucosides from Lobelia sessilifolia and Adenophora spp. (Campanulaceae), Carbohydr. Res. 323 (2000) 73–80. [53] Y. Jiang, R. Shi, B. Liu, Q. Wang, Y. Dai, Studies on chemical components of Lobelia chinensis, Zhongguo Zhong Yao Za Zhi 34 (2009) 294–297. [54] J. Sun, X. Wang, H. Zhang, J. Yang, A new triterpenoid ester from Lobelia sessilifolia, Chem. Nat. Compd. 48 (2012) 416–418, https://doi.org/10.1007/s10600-0120263-8. [55] K. Ishimaru, H. Yonemitsu, K. Shimomura, Lobetyolin and lobetyol from hairy root culture of Lobelia inflata, Phytochemistry 30 (1991) 2255–2257, https://doi.org/10. 1016/0031-9422(91)83624-T. [56] Y. Zhou, Y. Wang, R. Wang, F. Guo, C. Yan, Two-dimensional liquid chromatography coupled with mass spectrometry for the analysis of Lobelia chinensis Lour. Using an ESI/APCI multimode ion source, J. Sep. Sci. 31 (2008) 2388–2394, https://doi.org/10.1002/jssc.200700685. [57] P.P. Wang, J. Luo, M.H. Yang, L.Y. Kong, Chemical constituents of Lobelia chinensis, Chin. Tradit. Herb. Drug 44 (2013) 794–797. [58] J.-J. Lu, J.-L. Bao, X.-P. Chen, M. Huang, Y.-T. Wang, Alkaloids isolated from natural herbs as the anticancer agents, Evid. Based Complement. Alternat. Med. 2012 (2012) 1–12, https://doi.org/10.1155/2012/485042. [59] R. Charlier, R. Tondeur, Alcaloides de lobelia-suavibracteata (haumann) extraction et etude pharmacologique, Arch. Int. Pharmacodyn. Ther. 83 (1950) 193–195. 38