Encyclopedia
Please note this is a comparison between Version 1 by Luis Alberto Mejía-Manzano and Version 2 by Rita Xu.
Native Mexican plants are a wide source of bioactive compounds such as pentacyclic triterpenes. Pentacyclic triterpenes biosynthesized through the mevalonate (MVA) and the 2-C-methyl-D-erythritol-phosphate (MEP) metabolic pathways are highlighted by their diverse biological activity. Compounds belonging to the oleanane, ursane, and lupane groups have been identified in about 33 Mexican plants, located mainly in the southwest of Mexico. 45 compounds pentacyclic triterpenes were reported showing antiinflammatory, cytotoxic, anxiolytic, hypoglycemic, and growth-stimulating or allelopathic activities. Extraction is essentially performed by maceration and Soxhlet with organic solvents and consecutive chromatography of silica gel have been used for their whole or partial purification. Nanoparticles and nanoemulsions are the vehicles used in Mexican formulations for drug delivery of the pentacyclic triterpenes until now. Sustainable extraction, formulation, regulation, isolation, characterization, and bioassay facilities are areas of opportunity in pentacyclic triterpenes research in Mexico while the presence of plant and human resources and traditional knowledge are strengths.
Native Mexican plants are a wide source of bioactive compounds such as pentacyclic triterpenes. Pentacyclic triterpenes biosynthesized through the mevalonate (MVA) and the 2-C-methyl-D-erythritol-phosphate (MEP) metabolic pathways are highlighted by their diverse biological activity. Compounds belonging to the oleanane, ursane, and lupane groups have been identified in about 33 Mexican plants, located mainly in the southwest of Mexico. 45 compounds pentacyclic triterpenes were reported showing antiinflammatory, cytotoxic, anxiolytic, hypoglycemic, and growth-stimulating or allelopathic activities. Extraction is essentially performed by maceration and Soxhlet with organic solvents and consecutive chromatography of silica gel have been used for their whole or partial purification. Nanoparticles and nanoemulsions are the vehicles used in Mexican formulations for drug delivery of the pentacyclic triterpenes until now. Sustainable extraction, formulation, regulation, isolation, characterization, and bioassay facilities are areas of opportunity in pentacyclic triterpenes research in Mexico while the presence of plant and human resources and traditional knowledge are strengths. The present review discusses the generalities of the pentacyclic triterpene (definition, biogenic classification, and biosynthesis), a summary of the last two decades of research on the compounds identified and their evaluated bioactivity, the generalities about the extraction and purification methods used, drug delivery aspects, and a critical analysis of the advantages and limitations of research carried out in this way.
- pentacyclic triterpenes
- Mexican plants
- biological activity
- extraction
- purification
- drug delivery
1. Introduction
Mexico belongs to the “megadiverse” group of countries and due in part to its wide plant biodiversity. It is estimated that Mexico possesses between 21,989 and 23,424 vascular plant species, placing the country in the 5th position within this category [1][2][1,2]. Approximately, 40% of this flora is endemic and 17% (around 4000 species) is believed to have medicinal properties [3]. Generally, medicinal plants have a wild origin and many of these have been employed for centuries for the treatment of diverse illnesses ranging from acute problems to severe or chronic disorders. However, not all these plants have been discovered, characterized, and/or studied.
It is well known that medicinal plants are an inexhaustible source of chemical compounds with potential therapeutic effects. In this context, one of the groups of phytochemicals highlighted by their diverse biological activity are triterpenes, which have displayed anti-inflammatory, analgesic, antibiotic, antiviral, antimycotic, immunomodulator, hepatoprotective, hemolytic, cytostatic, and anticancer properties, the latter by exerting antiangiogenic, proapoptotic, and prodifferentiative effects [4][5][4,5]. Specifically, pentacyclic triterpenes (PCTs) are a subgroup of triterpenes that present some of these properties and are attracting scientific attention for their potential use as therapeutic agents [6][7][6,7].
1.1. General Overview of Pentacyclic Triterpenes
1.1.1. Structure, Classification, Distribution, and Biological Importance
Pentacyclic triterpenes (PCTs) are subcategorized inside the triterpenoid cluster and are heterogeneous compounds of 30 carbon atoms [8] belonging to the general group of compounds called terpenes, whose basic subunit is isoprene (methyl-1,3-butadiene). In general, terpenes composed of two isoprene units are called monoterpenoids (10 C), those with three units are known as sesquiterpenoids (15 C), those with four units as diterpenes (20 C), and those with more than four subunits are classified as polyterpenes [9]. Triterpenes are considered polyterpenes because they present six isoprene units. Both sesquiterpenes and polyterpenes are produced in the plant’s cytosol while the majority of diterpenes and tetraterpenes (40C) have their origin in plastids [10].
On their part, PCTs are molecules with a backbone based on five six-member rings or four cyclohexanes and one cyclopentane. Ursane, oleanane, taraxastane, gammacerane, and friedelane are PCTs made from five six-member rings while lupane and hopane are groups based on four six-member rings and a final five-member ring (Figure 1) [6][11][12][6,11,12]. The classification criteria for the establishment of these triterpene groups are based on biogenetic principles [11]. PCTs are widely distributed in nature and are present in fruit peel, stem bark, and leaves [11][13][11,13]. In addition, these can be found in their free form, as esters or as saponins (i.e., combined with other sugars) [11].
Figure 1. Pentacyclic triterpene backbone classification and representative subgroups: oleanane (A), ursane (B), and lupane (C).
In the last years, several beneficial activities of PCTs with medical importance have been described, including anti-inflammatory, antibacterial, antiviral, anti-parasitic, anticancerogenic, antidepressant, anti-anxiety, neuroprotective, cardioprotective, and immunomodulatory effects [6][14][15][16][6,14,15,16] Moreover, triterpenes from the lupane, oleanane, and ursane groups have received special attention because of their pharmacological effects, coupled with their low toxicity [13]. Naturally, PCTs are produced as a defense against metabolic oxidations and some other factors such as microorganisms or environmental stress [17]. The bioactivity of the triterpenes is highly affected by its backbone and the position and number of chemical groups (i.e., alkyl, hydroxyl, carbonyl, and aminoacids) in their structure [18]. It is important to point out that many of these PCTs, because of the complexity of their structure, have not yet been chemically synthesized.
1.1.2. Biosynthesis
The isoprene units integrating triterpenes are biosynthesized by two metabolic pathways: the mevalonate (MVA) pathway and the 2-C-methyl-D-erythritol-phosphate (MEP) pathway. The MVA pathway occurs in the cytosol from pyruvate and glyceraldehyde 3-phosphate while the MEP pathway occurs in the plastids [19] from 3 acetyl-CoA molecules [20]. The objective of both routes is to produce IPP (isopentenyl diphosphate), a molecule that contains the required isoprene backbone for terpenoid synthesis (Figure 2). On its part, this backbone can be transported between plastids and the cytosol, enabling interactions between both routes [21]. IPP is isomerized to dimethylallyl diphosphate (DMAPP), and this isomer is condensed with another molecule of IPP to produce geranyl diphosphate (GPP), a compound of 10 carbons. If another IPP molecule is added to GPP, farnesyl diphosphate (FPP) with 15 carbons is obtained. The subsequent addition of an IPP unit generates the 20-carbon geranylgeranyl diphosphate (GGPP). These building blocks are the precursor structures of the different terpene groups [22]. The combination of two FPP units through the squalene synthase enzyme forms squalene (30 carbons). In the next step, squalene is turned into squalene epoxide (2,3-oxidosqualene) by squalene monoxigenase and the latter is cyclized with a subsequent structure rearrangement [11][23][11,23], which can be turned into a variety of polycyclic triterpenes depending on the enzymes involved, called oxidosqualene cyclases (OSCs) [24]. However, prior to the action of OSCs, the 2,3-oxidosqualene must adopt a chair-chair-chair (CCC) conformation, with this being a key step in which the synthesis is oriented towards triterpenes, having the dammarenyl cation as an initial intermediate. Otherwise, if the 2,3-oxidosqualene adopts a chair-boat-chair (CBC) conformation, the synthesis is directed to sterols through the protosteryl cation as the main intermediary [23]. Recently, this dichotomy has been questioned because a mutant rice OSC (which normally produces a sterol) yielded a novel PCT with an architecture that is more related to the dammarenyl cation or even to an undescribed third cation [25].
Figure 2. Biosynthetic pathway of PCTs in plants through the mevalonate (MVA) pathway and 2-C-methyl-D-erythritol-phosphate (MEP) pathway, showing the initial substrates, squalene synthesis, and cyclizing and rearrangement of cations that result in the diverse groups of PCTs.
Considering the formation of PTCs from the CCC conformation, OSCs start the cyclization with the protonation of the final double bond in the 2,3-oxidosqualene. The variation in carbocation cyclization and backbone rearrangements generate the diverse groups of PTCs [23][26][23,26]. So, the dammarenyl cation can be expanded from C20 to C18, forming a baccharenyl cation. Another ring expansion to C20 generates a compound of five rings known as the lupyl cation [27], which is the backbone of the lupane group. When the E ring in the lupyl cation suffers an expansion and the carbocation migrates to C19, the germanicyl cation is formed. From this intermediary, the cation re-location to C14 and a methyl shift produces the precursor of ursanes. Additionally, the oleanyl cation is rendered from the germanicyl cation, containing the C13 cation in the same way as the ursanyl cation but with two methyl groups in the C20 position instead of a methyl group in C19 and another in C20. The next biosynthesized backbone intermediary from the oleanyl cation is the taraxeryl cation with the cation in C14. If the carbocation migrates to C8, the multiflorenyl cation is produced. When the carbocation is in C9 or C10, the walsurenyl or companulyl cations are produced, respectively. The displacement to the C5 results in a glutinyl cation. Finally, the last PCT and most rearranged (friedelanes) group is formed through the friedelyl cation with the carbocation in the C4 position (Figure 2).
OSCs are encoded by many genes in plants and many of these enzymes may participate in the formation of multiple products [23]. The structure diversification in these groups of PCTs is achieved by modifications of each scaffold base such as oxygenation (i.e., addition of functional groups carbonyl, aldehyl, hydroxyl, carboxyl, and epoxy groups), glycosylation, and acylation. The oxygenation reactions are catalyzed by cytochrome P450 monooxygenases (P450s). Until 2017, about 55 P450s related to PCT biosynthesis in plants had been identified, which belonged to the CYP716, CYP51, CYP71, CYP72, CYP87, CYP88, and CYP93 families [28]. It is important to clarify that complete biosynthetic pathways of specific PCTs have not been completely elucidated yet; hence, a large amount of PCTs may still be discovered.
2. Pentacyclic Triterpenes from Mexican Plants
Different scientific repositories were selected to find reports regarding PCTs from Mexican plants. The terms “pentacyclic triterpenes” AND “Mexican plants” OR “Mexican” OR “Mexico” OR “bioactivity” were used in the search queries, and from the obtained results, research articles that evaluated the biological activity of isolated PCTs or tested extracts containing PCTs during the last 22 years were selected. In several cases, PCT-producing plant species are spread worldwide, but rwesearchers attempted to focus on the biological diversity present in Mexico. As a result, researcherswe found 31 reports of bioactivity studies. The location of the studied plants was established according to the recollection data (when available) and the species’ distribution reported by public organisms and/or scientific sources. So, the plant geographical location by state in these research studies related to 346 absolute hits. The tendencies in the distribution (Figure 3) show that higher hits of the investigated plants are found in the southwest and center of México, which correlates with the high biodiversity of Mexico in this zone.
Figure 3. Geographical origin and distribution of Mexican plants as a source of PCTs with bioactivity according to published reports and distribution frequencies.
Biological Activity Survey of PCTs Found in Mexican Plants
A summary of the different reported bioactivities of PCTs found in Mexican plants is presented in Table 1. Figure 4 presents the structure of the PCTs used in the discussion of the following subsections, with the corresponding structure indicated by the bold numbers in parentheses in the next lines.
Figure 4. Chemical structures of PCTs identified in native Mexican plants.
Table 1. PCTs isolated from Mexican plants with biological activity.
| Plant Species | Identified Compounds | Subgroup | Activities | References |
|---|---|---|---|---|
| Lantana hispida | Oleanolic acid | Oleanane | Antimicrobial activity (MIC) on Mycobacterium tuberculosis: • H37Rv: 25 μg/mL • STR-R, RIF-R, INH-R, and EMB-R: 50 μg/mL |
[29] |
| 3-acetoxy-22-(2′-methyl-2Z-butenyloxy)-12-oleanene | Oleanane | Antimicrobial activity (MIC) on M. tuberculosis: • H37Rv, STR-R, and INH-R: 25 μg/mL • RIF-R and EMB-R: 50 μg/mL |
||
| 3-hydroxy-22-(2′-methyl-2Z-butenoyloxy)-12-oleanen-28-oic acid (reduced lantadene A) | Oleanane | Antimicrobial activity (MIC) on M. tuberculosis: • H37Rv, STR-R, RIF-R, INH-R, and EMB-R: 50 μg/mL |
||
| Hippocratea excelsa | 21β-hydroxyolean-12-en-3-one | Oleanane | Antiprotozoal activity (IC50) on Giardia intestinalis: 27.4 μM | [30] |
| 21α-hydroxy-3-oxofriedelane | Friedelane | Antiprotozoal activity (IC50) on G. intestinalis: 19.8 μM | ||
| Pristimerine | Friedelane | Antiprotozoal activity (IC50) on G. intestinalis: 0.11 μM | ||
| Tingenone | Friedelane | Antiprotozoal activity (IC50) on G. intestinalis: 0.74 μM | ||
| Acacia cochliacantha | Lupenone | Lupane | Antimicrobial activity (MIC) on: • Staphylococcus aureus: 2.8 mg/mL • Bacillus subtilis: 1.4 mg/mL • Enterococcus faecium: 5.6 mg/mL • Lactobacillus plantarum: 11.3 mg/mL • Escherichia coli: 2.8 mg/mL • Salmonella typhirium: 22.5 mg/mL • Klebsiella pneumoniae: 22.5 mg/mL |
[31] |
| Taraxenone | Taraxerane | Antimicrobial activity (MIC) on: • S. aureus: 0.4 mg/mL • B. subtilis: 1.4 mg/mL • L. plantarum: 1.4 mg/mL • E. coli: 0.2 mg/mL • S. typhirium: 2.8 mg/mL • K. pneumoniae: 1.4 mg/mL • Pseudomonas aeruginosa: 2.8 mg/mL |
||
| Hippocratea excelsa | 11β,21β-dihydroxy-olean-12-ene-3-one | Oleanane | Antiprotozoal activity on Giardia intestinalis: IC50: 184.6 μM | [32] |
| 3α,11α,21β-trihydroxy-olean-12-ene | Oleanane | Antiprotozoal activity on G. intestinalis: IC50: 96.8 μM | ||
| 3α,21β-dihydroxy-11α-methoxy-olean-12-ene | Oleanane | Antiprotozoal activity on G. intestinalis: IC50: 690.7 μM | ||
| 3α,21β-dihydroxy-olean-9(11),12-diene | Oleanane | Antiprotozoal activity on G. intestinalis: IC50:78 μM | ||
| Chamaedora tepejiliote | Ursolic acid | Ursane | Antimicrobial activity (MIC) against M. tuberculosis: • H37Rv, INH-R, RIF-R, EMB-R, MMDO, and MTY147: 25 μg/mL • STR-R: 12.5 μg/mL In vitro intracellular load of M. tubrculosis MDR and H37Rv in macrophages at: • 6.25 μm/mL (14) + 12.5 μm/mL (1): (after 48 h) approximately 101 CFU/mL (both strains) • 0.625 μm/mL (14) + 1.25 μm/mL (1): (after 48 h) approximately 101 CFU/mL (H37Rv) Bacilli load per lung in mice model after 60 days of administration of 1:3 mixture of (1):(14) at 5 mg/kg • 0.1 × 106 bacilli/lung approximately • Control: approximately 0.9 × 106 bacilli/lung |
[33] |
| Lantana hispida | Oleanolic acid | Oleanane | Antimicrobial activity (MIC) against M. tuberculosis: • H37Rv, STR-R, MMDO, and MTY147: 50 μg/mL • INH-R, RIF-R and EMB-R: 25 μg/mL In vitro intracellular load of M. tubrculosis MDR and H37Rv in macrophages at: • 6.25 μm/mL: (after 24 and 48 h) approximately 105 CFU/mL. • 0.625 μm/mL: (after 48 h) approximately 105 CFU/mL • Control: approximately 106 CFU/mL Bacilli load per lung in mice model after 60 days of administration of 1:3 mixture of (1):(14) at 5 mg/kg • 0.1 × 106 bacilli/lung approximately• Control: approximately 0.9 × 106 bacilli/lung |
|
| Heterotheca inuloides | 3β-friedelinol | Friedelane | Antimicrobial activity (MIC) on Helicobacter pylori: >31.25 μg/mL | [34] |
| α-amyrin and β-amyrin | Ursane | |||
| Lantana camara | Lantanilic acid | Lantadene | Lehismaniacidal activity on L. mexicana: 9.50 ± 0.28 μM | [35] |
| Camaric acid | Lantadene | Lehismaniacidal activity on L. mexicana: 2.52 ± 0.08 μM | ||
| Lantadene B | Lantadene | Lehismaniacidal activity on L. mexicana: 23.45 ± 2.15 μM | ||
| Cisus incisa | α-amyrin-3-O-β-D-gluco pyranoside | Ursane | Antimicrobial activity (MIC) against carbapenems-resistant P. aeruginosa: 100 μg/mL | [36] |
| Cnidosculus spinosus | 3 β-acetoxy-hop-22(29)-ene | Hopane | Inhibitory activity on mouse edema at 0.31 μmol/ear: 57.27 ± 16.99% Inhibition of yeast α-glucosidase at 100 μM: 98.79% |
[37] |
| 3β-hydroxy-hop-22(29)-ene [Hopenol B] | Hopane | Inhibitory activity on mouse edema at 0.31 μmol/ear: 27.05 ± 7.38% Inhibition of yeast α-glucosidase at 100 μM: 23.47% Antiparasitic activity on Trypanosoma cruzi at 50 μM: <20% |
||
| 3-oxo-hop-22(29)-ene | Hopane | Inhibitory activity on mouse edema at 0.31 μmol/ear: 17.5 ± 4.11% Inhibition of yeast α-glucosidase at 100 μM:7.39% Antiparasitic activity on Trypanosoma cruzi at 50 μM: <20% |
||
| Agarista mexicana | 12-ursene | Ursane | Hypoglycemic activity on mice models after at 50 mg/kg: • 25.9 ± 6.1% glucose reduction |
[38] |
| Bursera copallifera | lupenone | Lupane | Anti-inflammatory activity in mouse edema inhibition at 1 mg/ear: 57.25 ± 1.36%, ID50: 1.052 μmol/ear Reduces NO production in LPS-stimulated macrophages: IC50: 20.08 ± 1.07 μM |
[39] |
| Bursera copallifera | α-amyrin | Ursane | Anti-inflammatory activity in mouse edema inhibition at 1 mg/ear: 25 ± 1.81%, ID50: >2.34 μmol/ear Reduces NO production in LPS-stimulated macrophages: IC50: 8.98 ± 1.73 μM |
[39] |
| α-amyrin acetate | Ursane | Anti-inflammatory activity in mouse edema inhibition at 1 mg/ear: 69.45 ± 1.8%, ID50: 1.17 μmol/ear Reduces NO production in LPS-stimulated macrophages: IC50: 22.47 ± 1.19 μM |
||
| 3-epilupeol | Lupane | Anti-inflammatory activity in mouse edema inhibition at 1 mg/ear: 66.39 ± 4.38%, ID50: 0.83 μmol/ear Reduces NO production in LPS-stimulated macrophages 15.50 ± 1.14 μM |
||
| 3-epilupeol formiate | Lupane | Anti-inflammatory activity in mouse edema inhibition at 1 mg/ear: 62.16 ± 1.8%, ID50: 0.96 μmol/ear Reduces NO production in LPS-stimulated macrophages 43.31 ± 2.60 μM |
||
| 3-epilupeol acetate | Lupane | Anti-inflammatory activity in mouse edema inhibition at 1 mg/ear: 49.35 ± 3.6%, ID50: >2.13 μmol/ear Reduces NO production in LPS-stimulated macrophages: IC50: 31.13 ± 1.25 μM |
||
| Bursera cuneata | α-amyrin | Ursane | Anti-inflammatory activity in mouse edema inhibition at 0.1 mg/ear: 44.9 ± 1.2% | [40] |
| Moronic acid | Oleanane | Anti-inflammatory activity in mouse edema inhibition at 0.1 mg/ear: 68.1 ± 1.3% Histamine inhibition in a mouse model at 0.1 mg/ear: 73.3 ± 1.1% Macrophages viability reduction at 60 μg/mL: 43% |
||
| Ursolic acid | Ursane | Anti-inflammatory activity in mouse edema inhibition at 0.1 mg/ear: 55.6 ± 2.1% |
||
| Sapium lateriflorum | 3β-palmitoyloxy olean-12-ene | Oleanane | In vitro cytotoxicity: inhibitory effect (%) at 50 μM • PC-3: 1.81 • K562: 6.88 • HCT-15: 10.46 •MCF-7: 3.24 • SKLU-1: 21.95 Anti-inflammatory activity in mouse edema inhibition at 1 μmol/ear: 48.26% |
[41] |
| Sapium lateriflorum | 3β-palmitoxlioxi-1β,11α-dihydroxi-olean-12-ene | Oleanane | In vitro cytotoxicity: inhibitory effect (%) at 50 μM • U251: 29.56 • PC-3: 20.72 • K562: 9.86 • HCT-15: 7.24 • MCF-7: 11.53 • SKLU-1: 12.89 Anti-inflammatory activity in mouse edema inhibition at 1 μmol/ear: 68.76% |
[41] |
| lupeyl palmitate | Lupane | In vitro cytotoxicity: inhibitory effect (%) at 50 μM • PC-3: 3.05 • K562: 3.46 • HCT-15: 10.24 •MCF-7: 13.43 • SKLU-1: 19.59 Anti-inflammatory activity in mouse edema inhibition at 1 μmol/ear: 22.31% |
||
| 3β-palmitoyloxy-11-oxo- olean-12-ene | Oleanane | In vitro cytotoxicity: inhibitory effect (%) at 50 μM • PC-3: 0.08 • HCT-15: 18.69 •MCF-7: 5.15 • SKLU-1: 20.06 Anti-inflammatory activity in mouse ear edema inhibition at 1 μmol/ear: 31.49%, ID50: 0.60 μmol/ear Anti-inflammatory activity in carrageenan-induced mouse plantar edema at 31.6 mg/kg: 48.2% after 3 h |
||
| Phoradendron reichenbachianum (Viscaceae) | Ursolic acid | Ursane | Vasorelaxant effect on rat aorta: EC50 11.7 μM, Emax 72.59% |
[42] |
| Moronic acid | Oleanane | Vasorelaxant effect on rat aorta: EC50 11.7 μM, Emax 92.01% |
||
| Morolic acid | Oleanane | Vasorelaxant effect on rat aorta: EC50 94.19 μM, Emax 73.75% |
||
| Betulinic acid | Lupane | Vasorelaxant effect on rat aorta: EC50 58.46 μM, Emax 79.01% |
||
| Cratageus gracilior | Corsolic acid | Ursane | Vasodilatory effect on rat aorta: EC50 108.9 ± 6.7 μM, Emax 96.4 ± 4.2% |
[43] |
| Galphimia glauca | Galphimidin | Nor-seco friedelane | Vasodilatory effect on rat aorta: EC50 145.9 ± 6.7 μM, Emax 99.5 ± 5.3% |
|
| Jatropha neupaciflora | 3β-trans-p-coumaroyl-oxy-16-β-hydroxy-20(29)-lupene | Lupane | Vasodilatory effect on rat aorta: 63.2 ± 5.8 μM EC50 and 27.5 ± 1.9% |
|
| Sebastiania adenophora | 3-epi-β-amyrin | Ursane | Approximate effect on root growth at 250 μg/mL • Lycopersicon esculentum: −21% • Echinocloa crus-galli: −36% • Amaranthus hypochondriacus: +55% |
[44] |
| β-amyrinone | Ursane | Approximate effect on root growth at 250 μg/mL • L. esculentum: −28% • E. crus-galli: −28% • A. hypochondriacus: +39% |
||
| 3-epi-lupeol | Lupane | Approximate effect on root growth at 250 μg/mL • L. esculentum: −32% • E. crus-galli: −9% • A. hypochondriacus: +47% |
||
| Lupenone | Lupane | Approximate effect on root growth at 250 μg/mL • L. esculentum: −36% • E. crus-galli: −5% • A. hypochondriacus: +27% |
||
| Taraxerol | Taraxerane | Approximate effect on root growth at 250 μg/mL • L. esculentum: −41% • E. crus-galli: −77% • A. hypochondriacus: +39% |
||
| Taraxerone | Taraxerane | Approximate effect on root growth at 250 μg/mL • L. esculentum: −49% • E. crus-galli: −44% • A. hypochondriacus: +23% |
||
| Galphimia glauca | Glaucacetalin E | Nor-seco friedelane | Anxiolytic effect on mice at 1, 10, and 30 mg/kg dose | [45] |
| Galphimidin B | Anxiolytic effect on mice at 1, 10, and 30 mg/kg dose | |||
| Galphimidin | Anxiolytic effect on mice at 1, 10, and 30 mg/kg dose |
One of the most evaluated properties is antimicrobial activity. In this regard, the team of Jiménez-Arellanes conducted the extraction of three oleanane-type triterpenoids from Lantana hispida: oleanolic acid (1) 3-Acetoxy-22-(2′-methyl-2Z-butenoyloxy)-12-oleanen-28-oic acid (2), 3-Hydroxy-22β-(2′-metyl-2Z-butenoyloxy)-12-oleanen-28-oic acid, and (3) reduced lantadene A [29]. These compounds were tested at a concentration ranging from 6.25 to 200 µg/mL against Mycobacterium tuberculosis H37Rv and its drug-resistant strains, with each one resistant to isoniazid, rifampin, streptomycin, and ethambutol, respectively. As a result, compound (1) showed a minimum inhibitory concentration (MIC) equal to 25 μg/mL on the H37Rv, and an MIC of 50 μg/mL when tested on the drug-resistant strains. Compound (2) showed an MIC of 25 μg/mL on the strains resistant to streptomycin and isoniazid, and an MIC of 50 μg/mL when tested on the H37Rv strain and those resistant to rifampin and ethambutol. Finally, compound (3) showed an MIC of 50 μg/mL against the five strains [29].
Another contribution to this field was performed by Mena-Rejón and collaborators [30]. They isolated 21β-hydroxyolean-12-en-3-one (4), 21α-hydroxy-3-oxofriedelane (5), pristimerine (6), and tingenone (7) from the root bark of Hippocratea excelsa. The activity against Giardia intestinalis was tested at a concentration for each compound in the range from 1.6 to 13.3 μg/mL with an inoculum of 5 × 104 trophozoites/mL, using metronidazole as the positive control. The results showed that compound (6) had the greatest activity (IC50 0.11 μM), followed by (7) (IC50 0.74 μM), (5) (IC5019.8 μM), and lastly, (4) (IC50 27.4 μM). Compounds (4) and (5) showed an inhibitory activity greater than metronidazole (IC50 1.23 μM) [30].
In another antimicrobial study, the authors isolated two PCTs from Acacia cochliacantha and tested its activity against Staphylococcus aureus, Bacillus subtilis, Enterococcus faecium, Lactiplantibacillus plantarum, Escherichia coli, Salmonella typhimurium, Klebsiella pneumoniae, and Pseudomonas aeruginosa [30]. Lupenone (8) had the highest MICs (22.5 mg/mL) against K. pneumoniae and P. aeruginosa while taraxerone (9) had a high MIC (2.8 mg/mL) against P. aeruginosa [31].
Cáceres-Castillo et al. found five PCTs in Hippocratea excelsa: (4), 11β,21β-dihydroxyolean-12-ene-3-one (10), 3α,11α,21β-trihydroxyolean-12-ene (11), 3α,21β-dihydroxy-11α-methoxyolean-12-ene (12), and 3α,21β-dihydroxyolean-9(11),12-diene (13) [32]. These compounds were tested in DMSO solution on Giardia intestinalis trophozoites in the log phase, except for compound (4), which was previously evaluated by Mena-Rejón et al. [29]. PCT (13) had the more significant and highest activity (IC50: 78, CI95: 77.2–79.1 μM), followed by (11) (IC50: 96.8, CI95: 96.8–99.2 μM), (10) (IC50: 184.6, CI95: 179.8–190.1 μM), and, lastly, (12) (IC50: 690.7, CI95: 650.6–736.9 μM). As a control, metronidazole showed an IC50 of 1.2 μM (CI95 of 0.88–1.59 μM) [32].
In the same field, the team of Jiménez-Arellanes extracted oleanolic acid (1) and ursolic acid (14) from Chamaedora tepejilote and Lantana hispida, respectively, performing distinct bioactivity assays [33]. Firstly, the compounds were tested in vitro individually and as a mixture against the Mycobacterium tuberculosis H37Rv strain (multidrug-resistant to isoniazid, rifampicin, ethambutol, and streptomycin) and four strains monoresistant to isoniazid, rifampicin, ethambutol, and streptomycin, respectively. Among all the tested strains, (14) had an MIC of 25 μg/mL, except for streptomycin-monoresistant M. tuberculosis, for which the MIC was 12.5 μg/mL. On the other hand, (1) showed the highest MIC at 50 μg/mL against the multidrug-resistant (H37Rv) and streptomycin-resistant strains. Additionally, both compounds were applied as a mixture, having an MIC of 12.5 μg/mL against the H37Rv strain and an MIC of 25 μg/mL on the other monoresistant strains. As part of this study, both (1) and (14) were tested against two clinical isolates: MMDO (resistant to isoniazid and ethambutol) and MTY 147 (resistant to isoniazid, rifampicin, ethambutol, and ethionamide), for which (14) showed a 25 μg/mL MIC whereas (1) showed an MIC of 50 μg/mL [33]. Secondly, five non-tuberculosis Mycobacterium species were used for the in vitro activity: M. chelonae, M. avium, M. fortuitum, M. smegmatis, and M. simiae. Compound (1) and the mixture of both acids had an MIC of 100 μg/mL on all species, whereas (14) showed the same MIC value on the first three species and 200 μg/mL for the last two species [33].
In addition, the same authors studied the activity of both compounds in a macrophage model considering the H37Rv strain and the MTY 147 clinical isolate [33]. For this purpose, macrophages (cell line J774A.1) were infected with both strains separately and treated with several combined ratios of the compounds. After several incubation times (3, 6, 24, and 48 h), the macrophages were lysed in order to measure the intracellular bacillus colony-forming units (CFU) inside them. After 48 h, the mixture (6.25 (14) + 12.5 (1) μmol/mL) had the highest reduction count (up to 101 CFU/mL) on the MDR isolate and the H37Rv strain (up in the same way as the mixture of 0.625 (14) + 1.25 (1) on the H37Rv strain). In this same study, the team infected BALB/c mice with the H37Rv strain, measuring the bacilli load per lung and the percentage of lung surface area affected by pneumonia after a mixture of both compounds was administered. Briefly, after 60 days of infection, 5 mg/kg of each triterpene was dissolved in ultra-pure olive oil and a total volume of 100 μL was administered subcutaneously to the mice (proportion 3:1 of (14) and (1)) 3 times a week for 30 and 60 days [33]. Over time, a decrement in the bacilli load was observed; after 60 days, the charge of the treated mice was approximately 0.1 × 106 bacilli/lung and near 0.9 × 106 bacilli/lung in the control mice. For the same period, the percentage of lung surface area affected by pneumonia was 11% and 32% for the treated and control mice, respectively. In the same experiment, the levels of the expression of the genes encoding IFN-γ, TNF-α, and iNOS were measured, concluding that animals treated with the mixture exhibited higher mRNA expression of IFN-γ and TNF-α; however, this was not statistically significant when compared to the control, whereas the iNOS mRNA expression was significantly higher than non-treated animals. Finally, the combination of the triterpene mixture with conventional chemotherapy (10 of triterpene mixture with conventional chemotherapy (10 μg/kg of rifampicin, 10 μg/kg isoniazid, and 30 μg/kg pyrazinamide)) was analyzed after 7, 14, 30, and 60 days of treatment. The lowest bacilli load per lung was observed on day 30 (approximately 0.003 × 106 bacilli/lung with respect to 0.005 × 106 bacilli/lung in the control population) in the PCTs mixture plus antibiotics. Instead, the lowest lung surface percentage affected by pneumonia occurred on day 60, with an approximate percentage of 13% with respect to 10% of mice treated only with antibiotics. At the transcriptional level, for IFN-γ, TNF-α, and iNOS, PCTs plus antibiotics induced high expression [33].
PCTs’ antimicrobial activity has also been analyzed by Egas et al., who extracted 3β-friedelinol (15) and a mixture of α-amyrin (16) and β-amyrin (17) from Heterotheca inuloides (Mexican arnica) and tested them against Helicobacter pylori, employing concentrations ranging from 1.95 to 31.25 μg/mL [34]. In this study, none of the tested concentrations showed a 100% bacterial inhibition of the bacterial growth and due to this reason, testing of the compounds at concentrations higher than 31.25 μg/mL is required to identify their respective MIC.
Lantanilic acid (18), camaric acid (19), and lantadene B (20) from Lantana camara var. aculeata (L.) were isolated and evaluated against Leishmania mexicana promastigotes and L. amazonensis amastigotes [35]. It is important to mention, prior to the isolation of the noted compounds, that a series of chromatographic fractions were proven. Both (18) and (19) acids, together with (20), were part of a chromatographic fraction (mixture) that led to an IC50 of 7.9 ± 0.3 and 11.2 ± 2.2 μg/mL against L. amazonensis and L. mexicana, respectively. Additionally, (18) and (19) in another fraction showed an IC50 of 23.6 ± 2.6 and 2.8 ± 0.5 μg/mL with the same species. Additionally, (20) was identified in a mixture, with an IC50 of 8 ± 1.1 and 22 ± 9.3 μg/mL on L. amazonensis and L. mexicana, respectively. As control drugs, pentamidine for L. amazonensis and Glucantime® (Sanofi-Aventis) for L. mexicana were used. In their isolated form, these PCTs had the following IC50s against L. mexicana: 9.50 ± 0.28 μM for (18), 2.52 ± 0.08 μM for (19), and 23.45 ± 2.15 μM for (20) while the reference drug had an IC50 of 11,000 ± 2.15 μM. In addition, the mixtures of the compounds presented a cytotoxic effect against BALB/c mouse peritoneal macrophages when tested from 12.5 to 200 μg/mL and a half maximal cytotoxic concentration (CC50) higher than 100 μg/mL [35].
Recently, a multi-institutional research group reported cytotoxic and antibacterial activity in Cisus incisa leaf extracts due in part to α-amyrin-3-O-β-D-glucopyranoside (21) among other phytocompounds [36]. For the antimicrobial testing, the team employed methicillin-resistant Staphylococcus aureus (MRSA), linezolid-resistant Staphylococcus epidermis (LRSE), vancomycin-resistant Enterococcus faecium (VREF), carbapenems-resistant Acinetobacter baumanii (CRAB), Escherichia coli producing extended-spectrum β-lactamase (ESBL), Pseudomonas aeruginosa resistant to carbapenems (PARC), carbapenems-resistant Klebsiella pneumoniae NDM-1 + (New Delhi metallo-β-lactamase) (KPNDM-1+), Klebsiella pneumoniae producer of ESBL (KPPB), and carbapenems-resistant Klebsiella pneumoniae producer of OXA-48 oxacillinase (KPOX). The phytochemicals were applied at 200, 100, 50, 25, 12.5, 6.25, and 3.12 μg/mL, using levofloxacin at the same doses and DMSO as the negative control. This study showed that compound (21) had an MIC of 100 μg/mL against PARC; however, all the other tested microorganisms showed an MIC higher than 200 μg/mL [36].
