# Traditional Medicinal Plants as a Source of Antituberculosis Drugs: A System Review

Authors: Yuhui Xu; Bowen Liang; Chengcheng Kong; Zhaogang Sun
Journal: BioMed Research International
 (2021)

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## Abstract

Medicinal plants are the chief components in the different oriental formulations in different traditional medical systems worldwide. As a thriving source of medicine, the medicinal plants with antituberculosis (TB) properties inspire the pharmacists to develop new drugs based on their active components or semimetabolites. In the present review, the anti-TB medicinal plants were screened from the scientific literatures, based on the botanical classification and the anti-TB activity. The obtained anti-TB medicinal plants were categorized into three different categories,viz., 159 plants critically examined with a total 335 isolated compounds, 131 plants with their crude extracts showing anti-TB activity, and 27 plants in literature with the prescribed formula by the traditional healers. Our systemic analysis on the medicinal plants can assist the discovery of novel and more efficacious anti-TB drugs.


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## Body

## 1. Introduction

Globally, traditional medicines (TM) make a vital contribution to the health care industry. In some countries, TM is the main source of health care or even the sole health care service available, especially in the rural sector [1]. The popularity of TM is also increasing in the developed countries for many different reasons, one of which is that the effectiveness of these TM was proved by the ethnopharmacological research. Early in 1972, the World Health Organization (WHO) established a Department of Traditional Medicine (DTM). Later, WHO (2013) called on to strengthen its public services of the traditional medicine [1]. Recently, the International Classification of Traditional Medicine (ICTM) was added as a new chapter into the International Classification of Diseases—11 (ICD-11) [2]. This achievement currently refers to the Traditional Chinese Medicine (TCM) alone, which opens its doors to accommodate many other thriving traditional health care philosophies prevailing globally, such as Ayurveda and Traditional African medicine (TAM).The spread of tuberculosis (TB) occurred from East Africa to the rest of the world with the migration of Homo sapiens, especially along the established trade routes with increased mingling and crowding of populations [3, 4]. Currently, there exist more than 10 million new cases of active disease and nearly 1.3 million deaths annually [5, 6]. In response to this spreading route, different countries developed their own traditional anti-TB formulations during the long courses in fighting this old plaque. Reports relating TB can be found in many ancestral data of the TM medical system, especially the TCM, Ayurveda, and TAM for its long history coexisting with human kinds for an estimated 70,000 years [7]. Investigations on the TM formulations show that the plants or herbs are the main composition of the traditional anti-TB formula, from which the active components or semimetabolites present a thriving source of new drugs. In the last 20 years, nearly 50% of drugs approved by the FDA in the United States of America have been derivatives of the natural products, including natural plant products [8]. Among the 435,000 plant species reported worldwide [9], an estimated 70,000 species of plants are used for medicinal purposes [10]. Thus, selecting plants based on ethnobotanical knowledge can enhance the probability to find new compounds with anti-TB activity.Before this review, some articles summarized the role of local medical plants but only few with anti-TB purpose [11, 12]. In this review, the anti-TB medicinal plants in different countries or regions are included to analyze their botanical classification, active botanical parts, extract method, and in vitro anti-TB activities in brief. Subsequently, the effective anti-TB plants are described with the following three branches: those with the isolated effective compounds, those with their crude plant extracts showing anti-TB effect, and those only found in the formula prescribed by traditional healers. Finally, we discuss the influencing factors on the development of traditional medicine and its future trend. This review is to inspire the development of possible new anti-TB agents derived from plants.


## 2. Brief Description of the Overall Anti-TB Medicinal Plants

We present the data by searching the main three databases: Wangfang Med, Chinese National Knowledge Infrastructure, and PubMed. Combinations of the following search terms are used: “tuberculosis,” “plant,” “herb,” “Chinese and western medicine,” and “random.” In the present review, only the nonrepetitive plant species with goodin vivo or in vitro anti-TB effect were accepted, although the criterion of the effectiveness was quite different with the inhibition concentration expressed in several different ways in different Mycobacteria, especially the M. tuberculosis H37Rv and the clinical isolates. The plants employed for treating the fever in traditional medicine have not been included, as fever is taken to be a nonspecific indication of many infections that are not restricted to TB. The exception to this is where fever is treated in conjunction with other TB-related symptoms like coughing.The classification of the traditional anti-TB medicinal plants in the present review belongs to 90 families including 230 genus and 277species (Figure1). The top 11 families with more than 7 plant species include Fabaceae (21 species in 18 genus), Asteraceae (20 in 16 genus), Euphorbiaceae (14 in 11 genus), Lamiaceae (13 in 11 genus), Rutaceae (14 in 10 genus), Combretaceae (9 in 4 genus), Piperaceae (9 in 1 genus), Zingiberaceae (8 in 3 genus), Annonaceae (7 in 6 genus), and Apiaceae (7 in 7 genus). Forty plant families are only reported once. A total of 6 Terminalia genus that belongs to the Combretaceae family have up to 6 anti-TB plant species, and about 9 anti-TB plant species belong to only one genus Piper.Figure 1
Classification of traditional anti-TB medicinal plants with effective crude extracts and the compounds. (a) Botanical families consisting of the anti-TB medicinal plants. There are 108 families including 230 genus and 277 species in this summary. (b) Genus number (>2) of the anti-TB medicinal plant families.
(a)(b)The literatures that we studied reported the anti-TB properties of the plant species from different plant parts (aerial parts, almonds, bark, bulbs, branches, fruits, flowers, heart woods, leaves, rhizomes, roots, stems, seeds, shoots, twigs, tubers, wood, whole plants, and even the ethnomedicinal recipes). With the leaves (83 cases), roots (61), aerial parts (32), barks (30), stems (14), whole plants (9), seeds (9), fruits (8), rhizomes (8), and flowers (7) are the top 10 most used anti-TB plant parts. For the same plant species, different parts of the plant presented a varied anti-TB effect. The useful plant parts of the genusLantana, Piper, and Terminalia mainly focused on the leaves, leaves, and both leaves and roots, respectively.It was observed that the extraction methods of the medicinal plants available in the literature significantly affected the anti-TB results. The general problems concerning the antibacterial screening of medicinal plant extracts have already been discussed in the literature [13]. There is still no single extraction method that is regarded as a standard for extracting the bioactive compounds from medicinal plants. One or more of the following solvents were mainly used in the studies: dichloromethane (268 times), methanol (65), ethanol (45), hexane (29), chloroform (18), ethyl acetate (11), water (11), and acetone (10), while diethylether, acetate, and hydroalcoholic solutions were seldom used. Since the extraction process deeply influences the results of the bioactivity tests and the subsequent isolation of bioactive compounds, selection of the best extraction method by consulting the traditional knowledge about the preparation of the herbal remedy remains crucial [14].As noted earlier and evidenced by this review, many reports lack adequate statistical analysis of their results and appropriate controls for their anti-TB activity, while some studies lack the generic extraction schemes or tests against a panel of various species ofMycobacteria to avoid false positive results. In this review, the parallel cytotoxic evaluation on mammalian cell lines has not been provided, since our main aim was to summarize the crude extracts or compound precursors of the anti-TB medicinal plants, although this needs to be overcome in the future.


## 3. Compounds from the Plants with Anti-TB Activity

Different from the conventional process of drug discovery involving the screening of large molecular libraries for biological activities and/or in silico data mining approaches based on cheminformatics modeling, the bioactivity-guided fractionation was mostly employed in medicinal plants to isolate the bioactive compounds. They were extracted first from the specified parts of the plants, then fractionized and characterized by infrared spectroscopy, mass spectrometry, and nuclear magnetic resonance spectroscopy, to obtain the structural data. Finally, their bioactivities were verified in different mycobacteria.Several groups summarized the active anti-TB natural products from the different organs and regions. Early in 2007, Copp and Pearce [15] summarized a total of 353 natural products (secondary metabolites) with reported growth inhibitory activity towards M. tuberculosis or related organisms from terrestrial and marine plants and animals and microorganisms. Abedinzadeh et al. [16] stressed the natural antimycobacterial peptides from bacteria, fungi, plants, and animals. Chinsembu [17] described the natural antimycobacterial agents from endophytes and medicinal plants in different regions of Africa, Europe, Asia, South America, and Canada. The present review only focused on the medicinal plants and the plants with anti-TB components belonged to the 156 species, 123 genus, and 64 families, of which Fabaceae (13 species, 10 genus), Rutaceae (10 species, 7 genus), and Lamiaceae (9 species, 7 genus) were the top three families; accordingly, more genera belong to those family with anti-TB activity (Table 1).Table 1
Medicinal plants and natural products showingin vitro anti-TB activity.
Plant speciesPlant familyPart usedExtractsCompound classActive constituentsReferencesAbrus precatoriusFabaceaeAerial partsDichloromethane fractionIsoflavanquinoneAbruquinone B (1) againstM. tuberculosis H37Ra with MIC of 12.5 μg/ml by MABAa,b[18]Acacia farnesianaMimosaceaeFruitMethanolic extractParabens, flavanonesMethyl gallate (2) showed activity against the sensible strainM. tuberculosis H37Rv with MIC of 50 μg/ml, respectively. The (2S)-Naringenin 7-O-β-galloylglucopyranoside (3) showed activity against multidrug resistant M. tuberculosis G122 with MIC of 50 μg/ml by MABA[19]Aglaia forbesiiMeliaceaeLeafDichloromethane fractionBenzopyran flavaglinesDesacetylpyramidaglain D (4) againstM. tuberculosis Ra with MIC of 25 μg/ml by MABA[20]Allanblackia floribundaGuttiferaeRoot barkSuccessively macerated in dichloromethane-methanol (1 : 1) and methanol for 4 hBiflavonoidsMorelloflavone (5) with the MIC of 19.53 and 39.06μg/ml against M. smegmatis and M. tuberculosis, respectively, by MABA[21]Allium neapolitanumAlliaceaeBulbChloroform extractCanthinoneCanthin-6-one (6), 8-hydroxy-canthin-6-one (7), and 5(ζ)-hydroxy-octadeca-6(E)-8(Z)-dienioc acid (8) with MICs in the range 8–32 μg/ml against a panel of fast-growing Mycobacterium species by dilution method[22]Allium sativumLiliaceaeBulbPetroleum ether extractFatty acidsLauric acid (9) and myristic acid (10) with MIC of 22.2 and 66.7μg/ml, respectively, against M. tuberculosis H37Ra by MABA[23]Allophylus edulisSapindaceaeLeafHydrodistillationCycloprop[e]azulen-4-olViridiflorol (11) against M. tuberculosis H37Rv (ATCC27294) with MIC of 190.0μg/ml by the microplate resazurin assay[24]Alnus incanaBetulaceaeBarkMethanol extractTriterpenesBetulin (12), betulinic acid (13), and betulone (14) with MIC of 12.5, 84, and 57μ g/ml against M. tuberculosis H37Ra by the microplate resazurin assay[25]Alpinia katsumadaiZingiberaceaeSeedn-HexaneDiarylheptanoidsTrans,trans-1,7-diphenylhepta-4,6-dien-3-one (15) as efflux inhibitors againstM. smegmatis mc2 155 by thiazolyl blue tetrazolium bromide method[26]Amphipterygium adstringensAnacardiaceaeStem barkDichloromethane/methanol (1 : 1)Tirucallanes(14β, 24E)-3-oxolanosta-7,24-dien-26-oic acid (16) and (14β,24E)-3-hydroxylanosta-7,24-dien-26-oic acid (17) with MIC of 64 and 32 μg/ml against M. tuberculosis H37Rv (ATCC 27294) by Bactec 460-TB apparatus[27]Amyris elemiferaRutaceaeLeafChloroform extractTexalinTexalin (18) with MIC of 25μg/ml against M. tuberculosis H37Rv by Bactec 460-TB radiometric methodology[28]Androsace umbellataPrimulaceaeWhole plantsEthanol extractSaxifragifolinSaxifragifolin D (19) reduced the intracellular replication ofM. tuberculosis in THP-1-derived macrophages but not in A549 cells[29]Angelica sinensisApiaceaeRootChloroform extractFatty diolFalcarindiol (20), 9Z,17-octadecadiene-12,14-diyne-1,11,16-triol,1-acetate (21), and oplopandiol (22) with MIC of 26.7, 25.3, and 50.2μg/ml, respectively, against M. tuberculosis H37Rv by MABA[30]Anisochilus harmandiiLamiaceaeAerial partsWaterDiterpenesOne pimarane-type diterpene named pimaric acid (23) and two abietane-type diterpenes named 9a,13a-epidioxyabiet-8 (14)-en-18-oic acid (24) and 15-hydroxydehydroabietic acid (25) with MIC of 50μg/ml, respectively, against M. tuberculosis H37Ra by MABA[31]Aralia nudicaulisAraliaceaeRhizomeMethanolic extractPolyacetylene(3R)-falcarinol (26) and (3R, 9R, 10S)-panaxydol (27) with MICs of 25.6μM and 36.0 μM and IC50fs of 15.3 μM and 23.5 μM against M. tuberculosis H37Ra by microplate resazurin assay[32]Ardisia gigantifoliaPrimulaceaeLeaves and stemsChloroform extractResorcinol5-alkylresorcinols (28), 5-(8Z-heptadecenyl) resorcinol (29), and 5-(8Z-pentadecenyl) resorcinol (30) with MIC of 34.4 and79.2μM against M. tuberculosis H37Rv (ATCC 27294) by MABA assay, respectively[33]Argyreia speciosaConvolvulaceaeRootMethanolic extractFlavanoid sulphatesQuercetin 3′7 di-O methyl 3-sulphate (31) and kaempferol 7-O methyl 3-sulphate (32) against M. tuberculosis H37Rv with MIC values of 25 μg/ml, respectively, by MABA[34]Arisaema siniiAraceaeWhole plant80% ethanolFatty acid ester(E)-2-(methyl (phenyl) amino) ethyl 2-(2-hydroxyundecanamido)-7 (33), 11-dimethyl-3-oxotetradec-4-enoate (34), and compound 1 inhibit mycobacterial biofilm formation, disperse the preformed biofilms, and disrupt the mature biofilms at concentration of 4, 8, and 32μg/ml, respectively[35]Aristolochia brevipesAristolochiaceaeRhizomeDichloromethane extractBenzo[f]-1,3-benzodioxolo[6,5,4-cd]indol-5(6H)-oneAristolactam I (35) with MIC of 12.5-25μg/ml against drug resistant M. tuberculosis by fluorometrit MABA[36]Aristolochia taliscanaAristolochiaceaeHook rootsHexanic extractNeolignansLicarin A (36), licarin B (37), and eupomatenoid-7 (38) with MIC of 3.12-12.5μg/ml against M. tuberculosis strains: H37Rv, four mono-resistant H37Rv variants and 12 clinical MDR isolates by MABA[37, 38]Arracacia tolucensisUmbelliferaeAerial partsDichloromethane–methanol (1 : 1)CoumarinsIsoimperatorin (39), osthol (40), suberosin (41), and 8-methoxypsoralen (42) with MIC of 64, 32, 16, and 128μg/ml against M. tuberculosis H37Rv (ATCC 27294) by MABA[39]Artemisia capillarisAsteraceaeAerial partsMethanol extractsStilbene derivativesUrsolic acid (43) and hydroquinone (44) with MIC of 12.5-25μg/ml against M. tuberculosis MDR/XDR strains by MABA[40]Artocarpus lakoochaMoraceaeRootDichloromethane extractBenzofuranLakoochin A (45) and lakoochin B (46) with MIC of 12.5 and 50μg/ml against M. tuberculosis H37Ra by MABA[41]Azorella compactaUmbelliferaeAerial partsn-HexaneDiterpenoidAzorellanol (47) and 17-acetoxy-13-alpha-hydroxy-azorellane (48) showed the strongest activity, with MIC of 12.5μg/ml against both strains (M. tuberculosis H37Rv (ATTC 27294) and a clinical isolate CIBIN/UMF15:99) by MABA[42, 43]Bauhinia purpureaFabaceaeRootDichloromethane extractDibenz[b,f]oxepinBauhinoxepin J (5,6-dihydro-3-methoxy-1,4-dionedibenz [b,f]oxepin (49) againstM. tuberculosis H37Ra with a MIC of 24.4 μM by MABA[44]Bauhinia saccocalyxFabaceaeRootDichloromethane extractDibenz[b,f]oxepinBauhinoxepins A (=3,3,5-trimethy lbenzo[b] pyrano[g] benzoxepin-6,11-diol) (50) and B (=6-methoxy-7-methyl-2-(3-methylbut-2-enyl)dibenzo[b,f]oxepine-1,8-diol (51) againstM. tuberculosis H37Rv with MIC of 6.25 and 12.5 μg/ml, respectively, by MABA[45]Beilschmiedia erythrophloiaLauraceaeRootMethanolEndiandric acidErythrophloin C (52) and suberosol B (53) againstM. tuberculosis H37Rv with MICs of 50 and 28.9 μg/ml, respectively, by MABA[46]Beilschmiedia tsangiiLauraceaeLeafMethanolEpoxyfuranoid lignansThree new epoxyfuranoid lignans, 4a,5a-epoxybeilschmin A (54) and B (55), and beilschmin D (56), together with known beilschmin A (57) and B (58) with MICs of 30, 40, 50, 2.5, and 7.5μg/ml, respectively, against M. tuberculosis 90-211378 by proportion method on agar[47]Blepharodon nitidumAsclepiadaceaeWhole plantEthanol extractHydroperoxycycloartanes24-Hydroperoxycycloart-25-en-3β-ol (59) and 25-hydroperoxycycloart-23-en-3β-ol (60) with MIC of 12.5 and 25 μg/ml against drug-resistant clinical isolates by MABA[48]Bocconia arboreaPapaveraceaeAerial partsChloroform extractDihydrochelirubineAlkaloids 6-methoxydihydrochelirubine (61) and 6-methoxydihydrocheleritrine (62) againstM. tuberculosis H37Rv and MDR tuberculosis with MIC of 12.5-50 μg/ml by MABA[49]Caesalpinia pulcherrimaFabaceaeRootDichloromethaneCassane-furanoditerpenoids6 Beta-benzoyl-7 beta-hydroxyvouacapen-5 alpha-ol (63) and 6 beta-cinnamoyl-7beta-hydroxyvouacapen-5 alpha-ol (64) with MIC of 25 and 6.25μg/ml against M. tuberculosis H37Ra by MABA[50]Caesalpinia sappanFabaceaeHeartwoodMethanolChalcone3-Deoxysappanchalcone (65) against both drug-susceptible and drug-resistant strains ofM. tuberculosis at MIC50s of 3.125–12.5 μg/ml in culture broth and MIC50s of 6.25–12.5 μg/ml inside macrophages and pneumocytes[51]Calliandra californicaFabaceaeRootEthyl acetateCassane-type diterpenesEscobarine A (66) and B (67) with MIC of 25-50μg/ml against M. tuberculosis H37Rv[52]Callicarpa pilosissimaVerbenaceaeLeaves and twigsMethanol extractDiterpenoids12-Deoxy-11,12-dihydro-seco-hinokiol methyl ester (68), callicarpic acid B (69), and alpha-tocopherol trimer B (70) with MICs ≤63.6μM against M. tuberculosis H37Rv in vitro by MABA[53]Calophyllum lanigerumClusiaceaeAll plant materialsMethanolCoumarin(+)-Calanolide A (71) againstM. tuberculosis with H37Rv with MIC of 3.13 μg/ml by the radiometric BACTEC[54, 55]Camchaya calcareaAsteraceaeWhole plantDichloromethaneCyclodeca[b]furanGoyazensolide (72), centratherin (73), lychnophorolide B (74), isogoyazensolide (75), isocentratherin (76), 5-epi-isogoyazensolide (77), and 5-epi-isocentratherin (78) with MICs of 3.1, 3.1, 6.2, 1.5, 3.1, 3.1, and 3.1μg/ml, against M. tuberculosis H37Rv, respectively, by MABA[56]Celastrus vulcanicolaCelastraceaeLeafDichloromethane extractSesquiterpenes1α-Acetoxy-6β, 9β-dibenzoyloxy-dihydro-b-agarofuran (79) with MIC value of 6.2 μg/ml against sensitive and resistant M. tuberculosis strains by MTT method[57]Chamaedorea tepejiloteArecaceaeLeafHexane extractsPentacyclic triterpenes, fatty alcoholsUrsolic acid (43) and farnesol (80) againstM. tuberculosis H37Rv (ATCC 27294) with MIC of 50 μg/ml and 8 μg/ml, respectively, by MABA[58, 59]Chrysanthemum morifoliumAsteraceaeFlowerMethanol extract3-Hydroxy triterpenoidsManiladiol (81), 3-epilupeol (82), and 4,5a-epoxyhelianol (83) with MIC of 4μg/ml, 4 μg/ml, and 6 μg/ml, respectively, against M. tuberculosis H37Rv by MABA[60]Citrullus colocynthisCucurbitaceaeFruitMethanolic extractTriterpenesUrsolic acid (43) and cucurbitacin E 2-0-β-D-glucopyranoside (84) against M. tuberculosis H37Rv with MICs0f50 and 25 μg/ml, respectively, by BACTEC 460TB system[61]Citrus aurantiifoliaRutaceaeFruit peelsHexane extractFuro[3,2-G]coumarin, fatty acidBoth 5,8-dimethoxypsoralen (85) and palmitic acid (86) with the MIC of 25μg/ml against M. tuberculosis H37Rv (ATCC 27294) and M. tuberculosis H10 by MABA[62]Clausena excavataRutaceaeRhizomeChloroform extractCoumarins, carbazole derivativesDentatin (87), nor-dentatin (88), clausenidin (89), 3-formylcarbazole(90), mukonal (91), 3-methoxycarbonylcarbazole (92), 2-hydroxy-3-formyl-7-methoxycarbazole (93), and clauszoline J (94) with MIC of 50, 100, 200, 100, 200, 50, 100, and 100μg/ml against M. tuberculosis H37Ra by MABA[63]Clavija proceraTheophrastaceaeStem and barkEthanol extractOleanane triterpeneOleanane triterpenoid aegicerin (95) with MIC values ranged between 1.6 and 3.12μg/ml against 37 different sensitive and resistant MTB strains by thiazolyl blue tetrazolium bromide method[64]Clinacanthus siamensisAcanthaceaeLeafEthanolAmideTrans-3-methylthioacrylamide (96) with the MIC of 200μg/ml against M. tuberculosis H37Ra by MABA[65]Cnidoscolus chayamansaEuphorbiaceaeLeafChloroform : methanol (1 : 1)Pentacyclic triterpenesMoretenol (97) and moretenyl acetate (98) showed MIC of 25μg/ml against M. tuberculosis H37Rv and four monoresistant strains[66]Combretum molleCombretaceaeStem barkAcetonePolyphenolPunicalagin (99) with MIC of 600μg/ml against M. tuberculosis H37Rv by the agar proportional method[67, 68]Cordia globiferaEhretiaceaeRootA hexane-soluble extractQuinonesGlobiferin (100) and cordiachrome C (101) with MICs of 6.2 and 1.5μg/ml, respectively, against M. tuberculosis H37Ra by MABA[69]Croton kongensisEuphorbiaceaeLeafDichloromethaneDiterpenedione16-Dien-9,15-dione (102), ent-8,9-seco-8,14-epoxy-7R-hydroxy-11â-acetoxy-16-kauren-9,15-dione (103), ent-8,9-seco-7R-hydroxy-11â-acetoxykaura-8 (14) with MICs of 25.0, 6.25, and 6.25μg/ml, respectively, and possessed antimalarial activity with IC50 ranges of 1.0-2.8 μg/ml against M. tuberculosis H37Ra by MABA[70]Curcuma longaZingiberaceaeRhizomesChloroform extractsCurcuminCurcuminoid demethoxycurcumin (104) with MIC of 200μg/ml against M. tuberculosis H37Rv by BACTEC 460[71, 72]Curtisia dentataCurtisiaceaeLeafEthanol extractsTriterpenesUrsolic acid acetate (105) and betulinic acid acetate (106) with MIC of 3.4μg/ml and 19.8 μg/ml against M. tuberculosis H37Rv (ATCC 27294) by MABA[73]Cynanchum atratumAsclepiadaceaeRootsEthanol extractIsoquinolin(-)-Deoxypergularinine (107) with MIC of 12.5μg/ml against M. tuberculosis H37Ra, H37Rv, MDR, and XDR strains by Bactec MGIT 960TM[74]Derris indicaFabaceaeStem, rootHexane : dichloromethane (1 : 1)Flavonoids3-Methoxy-(3″,4″-dihydro-3″,4″-diacetoxy)-2″,2″-dimethylpyrano-(7,8 : 5″,6″)-flavone (108), 3,4-methylenedioxy-10-methoxy-7-oxo[2]benzopyrano[4,3-b]benzopyran (109), karanjachromene (110), and pinnatin (111) against M. tuberculosis H37Ra with MICs of 25, 6.25, 12.5, and 12.5 μg/ml by MABA[75, 76]Diospyros anisandraEbenaceaeStem barkn-Hexane extractNaphthalenePlumbagin (112) and 3,3′-biplumbagin(113) against M. tuberculosis H37Rv with MIC of 1.56 and 3.33 μg/ml by MABA[7]Diospyros decandraEbenaceaeBarkHexaneTriterpenes2-Oxo-3b,19a-dihydroxy-24-nor-urs-12-en-28-oic acid (114) with MIC ofμg/ml against M. tuberculosis H37Ra by MABA[77]Diospyros montanaEbenaceaeStem barkChloroform extractQuinonoidsPlumbagin (112) > emodin (115) > menadione (116) > thymoquinone (117) > diospyrin (118) againstM. tuberculosis H37Ra (ATCC 25177) and MDR-TB by MABA[78, 79]Disthemonanthus benthamianusFabaceaeStem barkMethanol extractFlavonoidsDistemonanthoside (119), sitosterol 3-O- -d-glucopyranoside, 4-methoxygallic acid (118), and quercetin (121), against a clinical isolate strain ofM. tuberculosis AC 45 with MIC ranged from 31.25 to 125 μg/ml by MABA[80]Dracaena angustifoliaDracaenaceaeLeafDichloromethane extractTriterpenes, fatty acids, fatty alcoholsErgosterol-5,8-endoperoxide (122), linoleic acid (123), and E-phytol (124) withMICs≤2 μg/ml against M. tuberculosis H37Rv (ATCC 27294) by MABA[81]Ehretia longifloraBoraginaceaeRootMethanolic extractQuinoneEhretiquinone (125) and prenylhydroquinone (126) with MIC of 25 and 26.2μg/ml against M. tuberculosis strain H37Rv by the agar proportion method[82]Engelhardia roxburghianaJuglandaceaeRootMethanolQuinoneEngelharquinone (127), 3-methoxyjuglone (128), and (-)-4-hydroxy-1-tetralone (129) with MIC of 3.125, 3.125, and 6.25μg/ml against M. tuberculosis 90-221387 and 0.2, 0.2, and 4.0 μg/ml against M. tuberculosis H37Rv, respectively, by agar proportion method[83, 84]Eriosema chinenseFabaceaeRootExane and dichloromethane extractsFlavonoidsKhonklonginol A (130), B (131), H (132), and lupinifolinol (133), dehydrolupinifolinol (134), flemichin (135), eriosemaone A (136), and lupinifolin (137), with MICs of 25, 50, 25, 25, 12.5, 12.5, 12.5, and 12.5μg/ml, respectively, against M. tuberculosis H37Ra by MABA[85]Erythrina gibbosaFabaceaeEthnomedicinal recipes70% aqueous methanolIsoflavonoidsIsoflavonoidspasellidin (138) and erythobissin (139) with MICs, respectively, lying between 8μg/ml and 25 μg/ml against MTB; 3-phenyl coumarin derivative indicanine (140) with MIC of 18.5 μg/ml against M. smegmatis by agar proportion method[86]Erythrina indicaFabaceaeRoot barkSuccessively extracted with dichloromethane–methanol (1 : 1) and methanolIsoflavonoidsIndicanine B (141) with MIC of 18.5μg/ml against M. smegmatis by agar proportion method[86]Erythrina senegalensisFabaceaeEthnomedicinal recipes70% aqueous methanolIsoflavonoidsIsoflavonoidspasellidin (138) and erythobissin (139) with MICs between 8μg/ml and 25 μg/ml against M. tuberculosis H37Rv; 3-phenyl coumarin derivative indicanine (138) with MIC of 18.5 μg/ml against M. smegmatis by agar proportion method[86]Eucalyptus torellianaMyrtaceaeLeafHexane extractFatty acid esterHydroxymyristic acid methylester (142) and a substituted pyrenyl ester (143), a sterol with MIC of 49.45 and 46.99μg/ml against M. tuberculosis H37Rv (ATCC 27294) by MABA[87]Euclea natalensisEbenaceaeRootAcetone extractNaphthoquinoneDiospyrin (118) and 7-methyljuglone (144) againstM. tuberculosis H37Rv (ATCC 27294) by BACTEC 460 with four- to sixfold reduction of MIC[88]Euphorbia ebracteolataEuphorbiaceaeRoots80% ethanolDiterpenoidsRosane-type diterpenoids 3 (145) and 8 (146) displayed moderate inhibitory effects on with the MIC of 18μg/ml and 25 μg/ml, respectively, by MABA[89, 90]Euphorbia lagascaeEuphorbiaceaeAir-dried powdered plantMethanol extractSteroidsErgosterol peroxide (147), cycloart-23-en-3β,25-diol (148), vanillin (149), and 4-hydroxybenzaldehyde (150) against M. tuberculosis H37Rv ATCC 27294 strain using two different systems: BACTEC 460TB (Bactec 460)[91]Exocarpos latifoliusSantalaceaeStemMethanol extractFatty acidExocarpic acid (E-octadeca-13-ene-9,11-diynoic-acid) (151) with MIC of 20μg/ml against M. tuberculosis H37Ra (ATCC 25177) by the thiazolyl blue tetrazolium bromide method[92]Fatoua pilosaMoraceaeWhole plantMethanol extractCoumarin; chalconesScopoletin (152), isobavachalcone (153) and (E)-1-[2,4-dihydroxy-3-(3-methylbut-2-enyl)phenyl]-3-(2,2-dimethyl-8-hydroxy-2H-benzopyran-6-yl)prop-2-en-1-one (154), copoletin (155), and umbelliferone (156) with MICs of 42, 18, 30, 42, and 58.3μg/ml against M. tuberculosis H37Rv by the agar proportion method[93]Ferula hermonisApiaceaeRootEthanol extractionOctahydroazulenJaeschkeanadiol benzoate (teferidin) (157) and jaeschkeanadiol p-hydroxybenzoate (ferutinin) (158) with MIC values of 3.125 and 1.56μg/ml against M. bovis BCG Pasteur 1173P2 and 0.69 and 2 μg/ml against M. tuberculosis H37Rv, respectively, by fluorescence assay[94]Garcinia livingstoneiGuttiferaeLeafAcetone extractFlavonoidsAmentoflavone (159) and 4-monomethoxy amentoflavone (160) with MIC of 0.6 ad 1.4 mg/ml againstM. smegmatis (ATCC 1441), with the positive control isoniazid (MIC=1.70 mg/ml) by tetrazolium violet indicator[95]Garcinia multifloraClusiaceaeHeartwoodMethanolBiflavones6,6″-Biapigenin hexamethylether (161), volkensiflavone hexamethylether (162), and hexamethylether of GB-1a (163) against M. tuberculosis H37Rv with inhibition of 96%, 95%, and 87% at 1.25 μg/ml by BACTEC 460TB[96]Garcinia nobilisClusiaceaeStem barkMethanolFlavonoids4-Prenyl-2-(3,7-dimethyl-2,6-octadienyl)-1,3,5,8-tetrahydroxyxanthone (164) with MIC of 8μg/ml against M. tuberculosis H37Rv ATCC 27294 and M. tuberculosis clinical MTCS2 by MABA[97]Goniothalamus laoticusAnnonaceaeFlowerEthyl acetate extractLactone derivative(+)-Altholactone (165) and howiinin A (166) with MIC of 6.25μg/ml, respectively, against M. tuberculosis H37Ra by MABA[98]Harrisonia perforataSimaroubaceaeBranchesEthanolic extractFlavonoidsPerforamone B (5-hydroxy-7-methoxy-2-methyl-8-(1-hydroxy-3-methyl-3-butenyl)chromone) (167) and D (2-hydroxymethylalloptaeroxylin) (168), peucin-7-methyl ether (169), and greveichromenol (170) with MICs of 25, 25, 50, and 50μg/ml against M. tuberculosis H37Ra by MABA[99]Helichrysum melanacmeAsteraceaeShootsAcetonic extractChalcone2,′4′,6′-Trihydroxy-3′-prenylchalcone (171) and 4′,6′,5″-trihydroxy-6″,6″-dimethyldihydropyrano-[2″,3″-2′,3′] chalcone (172) with MICs of 0.05 μg/ml against M. tuberculosis H37Rv by BACTEC radiometric method[100]Heracleum maximumApiaceaeRootMethanolic extractFuranocoumarins(3R,8S)-Falcarindiol (173) and 6-isopentenyloxyisobergapten (174) with MICs of 24μM and 167 μM and IC50s of 6 μM and 27 μM against M. tuberculosis H37Ra, respectively[101]Humulus lupulusCannabaceaeStrobile hopsHexane extractFatty acidUnsaturated fat oleic and linoleic acids (175) with MIC of 4 and 16μg/ml against M. fortuitum by thiazolyl blue tetrazolium bromide method[102]Hydnocarpus anthelminticaFlacourtiaceaeSeeds95% ethanolFatty acidAnthelminthicins A (176), B (177), C (178) (11-(cyclopent-1-en-1-yl)-11-oxoundecanoic acid, 2,3-dihydroxypropyl 9-[(R)-cyclopent-2-en-1-yl]nonanoate, 2,3-dihydroxypropyl 13-[(R)-cyclopent-2-en-1-yl]tridecanoate), and two known ones, namely, chaulmoogric acid (179) and ethyl chaulmoograte (180) with MIC of 5.54, 16.70, 4.38, 9.82, and 16.80μM, respectively, by GFP-expressed M. tuberculosis H37Rv[103]Hypericum perforatumGuttiferaeAerial partsHexane and chloroform extractsPyranoneHyperenone A (181) againstM. tuberculosis H37Rv and M. bovis BCG with MIC of 75 μg/ml and 100 μg/ml, respectively, by thiazolyl blue tetrazolium bromide method[104]Indigofera longeracemosaFabaceaeStemMethanol extractDiterpeneDiterpene 12-methyl-5-dehydroacetylhorminone (182) with MIC of 0.38μg/ml against M. tuberculosis H37Rv by proportion method[105]Ipomoea leptophyllaConvolvulaceaeLeafOrganic soluble extractTriterpenes3â,25-Epoxy-3R,21R-dihydroxy-22â-angeloyloxyolean-12-ene-28-oic acid (183), camaric acid (184), and rehmannic acid (185) with MICs of 64, 64, and 32μM, respectively, against M. tuberculosis H37Rv by BACTEC 460 radiometric system[106]Juniperus communisCupressaceaeNeedles and branchesMethanolic extractsDiterpeneIsocupressic acid (186) and communic acid (187) displayed MICs of 78μM and 31 μM against M. tuberculosis H37Ra, respectively, by microplate resazurin assay[107]Juniperus proceraCupressaceaeLeaf and bark95% ethanolDiterpenePlumbagin (112) and 7β-hydroxyabieta-8,13-dien-11,12-dione (188) with MIC<12.5 μg/ml against M. tuberculosis H37Rv by visible growth[108]Kaempferia galangaZingiberaceaeRhizomesAbsolute ethanolAromatic acidEthyl p-methoxycinnamate (189) inhibited the growth ofM. tuberculosis H37Ra and H37Rv with MICs of 48.5 and 24.2 mM by Bactec 460 system[109]Kaempferia parvifloraZingiberaceaeRhizomesWaterFlavonoids3,5,7,4′-Tetramethoxyflavone (190) and 5,7,4′-trimethoxyflavone (191) with MIC of 200 and 50 μg/ml, respectively, against M. tuberculosis H37Rv by MABA[110]Lantana hispidaVerbenaceaeAerial partsHexane extractPentacyclic triterpenoidsThree pentacyclic triterpenoids of 3-acetoxy-22-(2′-methyl-2Z-butenyloxy)-12-oleanen-28-oic acid (192), 3-hydroxy-22β-(2′-methyl-2Z-butenoyloxy)-12-oleanen-28-oic acid (reduced lantadene A) (193), and oleanolic acid (194) with MIC of 50, 50, and 25 μg/ml against M. tuberculosis H37Rv by MABA[111]Lantana horridaVerbenaceaeAerial partsHexanic extractsTriterpenesUrsolic acid (43) and oleanolic acid (194) againstM. tuberculosis H37Rv by MABA[58]Larrea divaricataZygophyllaceaeAerial partsDichloromethane/methanol (1 : 1)Flavone, polyphenols5,7-Dihydroxy-3-methoxy-2-(4-methox-yphenyl)-4H-chromen-4-one (195); 5,6,7-trihy-droxy-3-methoxy-2-(4-methoxyphenyl)-H-chromen-4-one (196);β,γ-dimethyl-,α,δ-bis(3,4-dihydroxyphenyl)butane (17) with MIC of 50 μg/ml, respectively, against M. tuberculosis H37Rv (ATCC 27294) by Bactec 460-TB apparatus[27]Ligusticum officinaleApiaceaeRootn-Hexane extractFatty alcoholFalcarindiol (198) with MIC of 20μg/ml and sesquiterpene alcohol a-prethapsenol (199) with MIC of 60 μg/ml against M. tuberculosis H37Rv by spot culture growth inhibition assay[112]Limnophila geoffrayiScrophulariaceaeAerial partsChloroform extractFlavonoidsLavonesnevadensin (5,7-dihydroxy-6,8,4′-trimethoxyflavone) (200) and isothymusin (6,7-dimethoxy-5,8,4′-trihydroxyflavone) (201) against M. tuberculosis H37Ra by MABA[113]Lippia turbinataVerbenaceaeAerial partsMethanol-dichlormethaneTriterpenoids3β,25-Epoxy-3α,21α-dihydroxy-22β-(3-methylbut-2-en-1-oyloxy) olean-12-ene-28-oic acid (202); 3β,25-epoxy-3α,21α-dihydroxy-22β-angeloyloxyolean-12-ene-28-oic acid (203); 3β,25-epoxy-3α,21α-dihydroxy-22β-tigloyloxyolean-12-ene-28-oic acid (204); and 3β,25-epoxy-3R-hydroxy-22β-(2-methylbutan-1-oyloxy)olean-12-ene-28-oic acid (205), lantanilic acid (206), camaric acid (184), lantanolic acid (207), and rehmannic acid (185) against M. tuberculosis H37Rv (ATCC 27294) using the radiorespirometric BACTEC 460 system[106]Litsea hypophaeaLauraceaeRootMethanolLactone, phenolLitseakolide L (208) and N-trans-feruloylmethoxytyramine (209) with MIC values of 25 and 1.6μg/ml, respectively, against M. tuberculosis H37Rv by agar proportion method[76]Lophira lanceolataOchnaceaeRootsMethanol extractFlavonoidsDihydrolophirone A (210) and lophirone A (211) with MIC of 31.25 and 15.75μg/ml against M. tuberculosis by MABA[114]Lunasia amaraRutaceaeLeafEthanolPhenyl quinoline4-Methoxy-2-phenylquinoline (212) and 4-methoxy-2-(3,4-ethylenedioxy) phenyl quinoline (213) with MICs of 16μg/ml, respectively, against M. tuberculosis H37Rv by BACTEC radiometric method[115]Marsypopetalum modestumAnnonaceaeStemEthanolDithiopyridineDipyrithione (214) withMIC<0.039 μg/ml, respectively, against M. tuberculosis H37Rv by MABA[116]Micromelum hirsutumRutaceaeStem barkDichloromethane extractCarbazoleMicromolide ((−)-Z-9-octadecene-4-olide) (215) and five known alkaloids: lansine (216), 3-formylcarbazole (90), and 3-formyl-6-methoxycarbazole (217) with MIC of 1.5, 31.5, 14.3, 42.3, and 15.6 μg/ml, against M. tuberculosis H37Rv by MABA[117]Microtropis fokienensisCelastraceaeRootMethanolSesquiterpenes1α-Acetoxy-2α-hydroxy-6β,9β,15-tribenzoyloxy-β-dihydroagarofuran (218), 2α-acetoxy-1α-hydroxy-6β,9β, 15-tribenzoyloxy-β-dihydroagarofuran (219), rbiculin G (220), and triptogelin G-2 (221) with MICs of 19.5, 15.8, 14.6, and 26 μM against M. tuberculosis 90-221387 by agar proportion method[118]Microtropis japonicaCelastraceaeStemMethanolSesquiterpenes15-Acetoxyorbiculin G (222), celahin C (223), salasol A (224), and 8-acetoxymutangin (225) with a MIC of 39.6μM, 15 μM, 15 μM, and 10 μg/ml, respectively, against M. tuberculosis H37Rv by agar proportion method[119, 120]Morinda citrifoliaRubiaceaeLeavesHexane fractionSteroidE-Phytol (mixture of the two ketosteroids, stigmasta-4-en-3-one (226) and stigmasta-4-22-dien-3-one (227)) and the epidioxysterol campesta-5,7,22-trien-3β-ol (228) with MIC of 2.5 μg/ml and minus 2.0 μg/ml against M. tuberculosis H37Rv (ATCC 27294) by the growth index[121, 122]Mulinum crassifoliumApiaceaeAerial partsn-HexaneDiterpenoid13-Hydroxy-mulin-11-en-20-oic-acid methyl ester (229), isomulinic acid n-propyl ester (230), and isomulinic acid n-butyl ester (231) with MIC of 6.25μg/ml, respectively, against M. tuberculosis H37Rv (ATCC 27294) by MABA[43]Myrtus communisMyrtaceaeLeafHydrodistillationMonoterpeneEssential oil of limonene (232), 1-8 cineole (233), andα-pinene (234) against M. tuberculosis H37Rv with MIC of 2% (v/v)[123]Nigella sativaRanunculaceaeSeedMethanolic extractQuinonesThymoquinone (TQ; 2-isopropyl-5-methyl-1, 4-benzoquinone) (117) with MIC of 12.5μg/ml intracellular M. tuberculosis H37Rv and extensively drug-resistant tuberculosis (XDR-TB) 72 h postinfection in RAW 264.7 cells[124]Ocimum basilicumLamiaceaeAerial parts (leaves, fruits, and flowers)Methanolic extractFatty acid ester(E)-3′-Hydroxy-4′-(1″-hydroxyethyl)-phenyl-4-methoxycinnamate (235) against M. tuberculosis H37Rv (ATCC 27294) by MABA[125]Ocimum sanctumLamiaceaeLeafEthanol extractTriterpenesUrsolic acid (UA, 3b-hydroxy-urs-12-en-28-oic-acid) (43) with MIC of 12.5μg/ml against M. tuberculosis by MABA[40, 126]Ocotea macrophyllaLauraceaeWood, leafEthanol extractApomorphine(S)-3-Methoxynordomesticine hydrochloride (236) with MIC of 4μg/ml against M. tuberculosis H37Rv by thiazolyl blue tetrazolium bromide method[127]Oplopanax horridusAraliaceaeInner stem barkConsecutively extracted with dichloromethane, methanol, and 50% aqueous methanolSesquiterpenesOplopandiol (237) and falcarindiol (198) with MI of 61.5 and 6.2μg/ml against M. tuberculosis (ATCC 35801) by MABA[128]Pedilanthus tithymaloidesEuphorbiaceaeRootSuccessively using hexane, dichloromethane, and methanolDiterpenoidCaniojane (238) againstM. tuberculosis H37Ra with MIC of 25 μg/ml by MABA[129]Phoradendron robinsoniiSantalaceaeWhole plantDichloromethane/methanol (1 : 1)Flavanone5-Hydroxy-2-(4′-hydroxyphenyl)-7-methoxy-2,3-dihydro-4H-chromen-4-one(239) with MIC of 128 μg/ml against M. tuberculosis H37Rv (ATCC 27294) by Bactec 460-TB apparatus[27]Physalis angulataSolanaceaeAerial partsChloroformPhysalinPhysalin D (240) with MIC of 32μg/ml against M. tuberculosis H37Rv ATCC 27294 by MABA[130]Piper chabaPiperaceaeRoot95% ethanolAmidePellitorine (241), guineensine (242), sarmentine (243), brachyamide B (244), 1-piperettyl pyrrolidine (245), sarmentosine (246), and 1-(3,4-methylenedioxyphenyl)-1E-tetradecene (247) with MIC values in the range of 25–200μg/ml against M. tuberculosis H37Ra by MABA[99, 131]Piper regnelliiPiperaceaeLeaves and stemsSupercritical fluid extraction (CO2 extracts)BenzofuranEupomatenoid-3 (248) and 5-(3-methyl-5-propylbenzofuran-2-yl) benzo[d][1,3]dioxole (249) againstM. tuberculosis H37Rv by colorimetric resazurin microtiter assay plate[132]Piper solmsianumPiperaceaeLeafMethanolic extractBenzofuranSynergism was observed inM. tuberculosis H37Rv and eight clinical isolates with eupomatenoid-5 (250) + rifampicin and in M. tuberculosis H37Rv and 17 clinical isolates with eupomatenoid-5+ ethambutol combinations[133]Plectranthus grandidentatusLamiaceaeAerial partsChloroformRoyleanoneAbietanes 6β,7α-dihydroxyroyleanone (251), horminone, and 6,7-dehydroroyleanone (252) with MIC of 25 and 12.5 μg/ml, respectively, against M. tuberculosis H37Rv by MTT[134]Plectranthus ornatusLamiaceaeAerial partsChloroformRoyleanone7α-Acetoxy-6β-hydroxyroyleanone (MIC 0.0083 μM) (253) and 6,7-dehydroroyleanone (MIC 0.039 μM) (254) against M. tuberculosis H37Rv by thiazolyl blue tetrazolium bromide method[134, 135]Plumbago indicaPlumbaginaceaeRootPetroleum etherNaphthalenePlumbagin (112) with MIC of 0.25 and 8μg/ml against MDR-TB and 2 and 4 μg/ml against the XDR-TB isolates by thiazolyl blue tetrazolium bromide method[78]Plumeria bicolorApocynaceaeLeavesChloroform extractNaphthalenePlumericin (112) against active and MDR TB with MIC of 0.12, 0.15, 0.07, 0.13, and 0.14μg/ml, respectively, better than isoplumericin[136]Polyalthia cerasoidesAnnonaceaeRootExtracted successively with hexane, ethyl acetate, and methanolApomorphine, fatty acid, sesquiterpenesBidebiline E (255), octadeca-9,11,13-triynoic acid (256), andα-humulene (257), with 6.25 μg/ml against M. tuberculosis H37Ra MABA[137]Polyalthia debilisAnnonaceaeRootMethanolLactone derivativeDebilisones B (258), C (259), and E (260) with MIC of 25, 12.5, and 25μg/ml, respectively, against M. tuberculosis H37Ra by MABA[138]Polyalthia evectaAnnonaceaeRootExtracted successively with hexane, dichloromethane, and methanolFuranFuranoid polyacetylene (261) with MIC of 3.1μg/ml against M. tuberculosis H37Ra by MABA[139]Potamogeton malaianusPotamogetonaceaeWhole plantDichloromethaneDiterpenesPotamogetonyde (262), potamogetonol (263), potamogetonin (264), and 15,16-epoxy-12-oxo-8 (17),13 (16),14-labdatrien-20,19-olide (265) with MIC of 50–100μg/ml against M. tuberculosis H37Ra by MABA[140]Pourthiaea lucidaRosaceaeLeafMethanolAlcohola-Tocospiro A (266) and B (267), a-tocopherylquinone (268), and (E)-phytol (124) with MICs of 30, 50, 25, and 12.5μg/ml against M. tuberculosis H37Rv by agar proportion method[141]Premna odorataLamiaceaeLeafMethanolAldehydes1-Heneicosyl formate (269) with MIC of 8μg/ml against M. tuberculosis H37Rv (ATCC27294) by MABA[142]Prunus cerasoidesRosaceaeRootSuccessively with hexane, ethyl acetate, and methanolFatty acidOctadeca-9,11,13-triynoic acid (256) with MIC of 6.25μg/ml against M. tuberculosis H37Ra by MABA[137]Punica granatumPunicaceaePeel of the fruitWaterPolyphenolEpigallocatechin-3-gallate (EGCG) (270) and quercetin (271) with MIC of MIC 32-256μg/ml against nine M. tuberculosis isolates by thiazolyl blue tetrazolium bromide method[143]Radermachera bonianaBignoniaceaeLeaves and twigsEthyl acetateSterolErgosterol peroxide (147) and b-sitostenone (272) with MICs of 34.8 and 9.9μM, respectively, against M. tuberculosis H37Rv by MABA[144]Ranunculus ternatusRanunculaceaeRootsEthanolBenzophenones(benzophenones) Methyl (R)-3-[2-(3,4-dihydroxybenzoyl)-4,5-dihydroxyphenyl]-2-hydroxypropanoate (273) with MIC of 41.67 μg/ml against M. tuberculosis H37Rv by MABA[145]Rumex hymenosepalusPolygonaceaeRootDichloromethane/methanol (1 : 1)Diphenylethylene5-[(E)-2-(4-Acetoxyphenyl) ethenyl]-1,3-benzenediol(1a) (274) with MIC of 32μg/ml against M. tuberculosis H37Rv (ATCC 27294) by Bactec 460-TB apparatus[27]Rumex nepalensisPolygonaceaeRootEthanol extractsGlycosideRumexneposide A (275), torachrysone (276), nepodin-8-O-b-D-glucopyranoside (277), torachrysone-8-O-b-D-glucopyranoside (278), and chrysophanol-8-O-b-D-glucopyranoside (279), which showed MICs of 20.7, 6.1, 26.6, 8.9, and 4.1μM, respectively, by fluorescence assay[146]Salvia africanaluteaLamiaceaeAerial partsEthanol extractDiterpeneAbietane-type diterpene carnosic acid (280) with MIC of 28μM against M. tuberculosis H37Rv (ATCC27294) by a rapid radiometric method[147]Salvia miltiorrhizaLamiaceaeRootsAcetoneTanshinonesTanshinone I (281), tanshinone IIA (282), and cryptotanshinone (283) with MIC in the range of 1.17–26.57μg/ml against M. tuberculosis H37Rv by agar proportion method[148, 149]Sapium indicumEuphorbiaceaeFruitHexane extractPhorbol esterSapintoxin A (284), sapintoxin B (285), 12-(2¢-N-methylaminobenzoyl)-4R-deoxy-5,20-dihydroxyphorbol-13-acetate (286), and 12-(2-methylaminobenzoyl)-4-deoxyphorbaldehyde-13-acetae (287) with MIC of 3.12, 12.5, 25, and 25μg/ml, respectively, against M. tuberculosis H37Ra by MABA[150]Saussurea lappaAsteraceaeBarkEthanol extractSesquiterpenoidsSaussureamine C (methyl 3-O-feruloylquinate) (288) againstM. tuberculosis by inhibiting folC[151]Scleropyrum wallichianumSantalaceaeTwigSuccessively with n-hexane, chloroform, and methanolFatty acidScleropyric acid (289) with MIC of 25μg/ml against M. tuberculosis H37Ra by MABA[152]Solanum torvumSolanaceaeFruitMethanol extractsXanthineMethyl caffeate (290) with MIC of 8μg/ml against M. tuberculosis by agar proportion method[153]Stephania dinklageiMenispermaceaeAerial partsChloroform extractFlavanoneFlavanone pinostrobin (291) againstM. tuberculosis H37Rv with MIC of 3.125 μg/ml by MABA[49]Strobilanthes cusiaAcanthaceaeLeafMethanol extractsQuinazolineTryptanthrin (292) with MIC of 1 mg/ml againstM. tuberculosis by BACTECH[154, 155]Tabernaemontana citrifoliaApocynaceaeLeafChloroform extractVoacangineIbogaine (293) and voacangine (294) with MIC of 50μg/ml against M. tuberculosis H37Rv by Bactec 460-TB radiometric methodology[28]Teloxys graveolensChenopodiaceaeAerial partsAcetone extractFlavanoneFlavanone pinostrobin (291) againstM. tuberculosis H37Rv with MIC of 12.5 μg/ml by MABA[49]Terminalia avicennioidesCombretaceaeRoot barkSuccessively with petroleum ether, ethyl acetate, chloroform, and methanolTriterpenesArjunolic acid (295) and friedelin (296) which, respectively, had MICs against BCG of 156μg/ml and 4.9 μg/ml, respectively, by broth microdilution method[156, 157]Terminalia browniiCombretaceaeRootMethanol extractFlavones, ellagic acidMethyl (S)-flavogallonate (297), ellagic acid xyloside (298), and methyl ellagic acid xyloside (299) againstM. smegmatis by measured spectrophotometrically at 620 nm[158]Byrsonima fagifoliaMalpighiaceaeLeafChloroform extractAmyrinα- and β-Amyrin (300), α-amyrin acetate (301), and dotriacontane (302) with MIC of 31.25, 62.5, and 62.5 μg/ml, respectively, against M. tuberculosis H37Rv (ATCC 27294) by MABA[159]Terminalia laxifloraCombretaceaeRootMethanol extractTriterpenes, fatty alcohol, sterolFriedelin (296), triacontanol (303),β-sitosterol (34), and sitostenone (35) with MIC of 250 μg/ml, 250 μg/ml, 500 μg/ml, and 500 μg/ml, respectively, against M. smegmatis by measured spectrophotometrically at 620 nm[158]Terminalia superbaCombretaceaeStem barkMethanol extractEllagic acid3,4′-Di-O-methylellagic acid 3′-O-β-D-xylopyranoside (306) and 4′-O-galloy-3,3′-di-O-methylellagic acid 4-O-β-Dxylopyranoside (307) with MIC of 4.88 μg/ml and 9.76 μg/ml, respectively, against M. tuberculosis H37Rv (ATCC 27294) by MABA[160]Tetracera potatoriaDilleniaceaeStem barkMethanol/dichloromethane (1 : 1)AlcoholTetraceranoate (308) and N-hydroxy imidate-tetracerane (309) with MIC of 7.8μg/ml and 15 μg/ml, respectively, against M. smegmatis (ATCC 23246) by tetrazolium method[161]Tetradenia ripariaLamiaceaeLeafHydrodistillationRoyleanone6,7-Dehydroroyleanone (254) with MIC of 31.2μg/ml against M. tuberculosis H37Rv by resazurin microtiter assay[162]Thalia multifloraMarantaceaeAerial partsDichloromethane–methanol (1 : 1) followed by a 100% methanolSteroidsStigmast-5-en-3β-ol-7-one (310), stigmast-4-ene-6β-ol-3-one (311), stigmast-5,22-dien-3β-ol-7-one (312), and stigmast-4,22-dien-6β-ol-3-one (313) were found to be the most active compounds with MIC of 1.9, 4., 1.0, and 2.2 μg/ml, respectively, against M. tuberculosis by fluorescence assay[163]Tiliacora triandraMenispermaceaeRootDichloromethaneBisbenzylisoquinoline alkaloidsTiliacorinine (314), 2′-nortiliacorinine (315), and tiliacorine (316) are bisbenzylisoquinoline alkaloids with MIC of 3.1–6.2 mg/ml against M. tuberculosis different strains by MABA[164]Tussilago farfaraAsteraceaeAerial partsSoxhlet extractedAromatic acidp-Coumaric acid (317) and 4-hydroxybenzoicacid (318) with MIC 31.3μg/ml of 62.5 μg/ml against M. tuberculosis H37Rv by high throughput spot culture growth inhibition assay[165]Ventilago madraspatanaRhamnaceaeStem barkMethanolAnthraquinoneEmodin (115) with MIC of 4μg/ml against M. tuberculosis H37Rv by MABA[78, 166]Zanthoxylum capenseRutaceaeLeaf80% ethanolPhenol, amideDecarine (319) and an N-isobutylamide, N-isobutyl-(2E,4E)-2,4-tetradecadienamide) (320) with MICof 1.6μg/ml against M. tuberculosis H37Rv by measuring the optical density at 600 nm in a Tecan M200 plate spectrophotometer[167]Zanthoxylum leprieuriiRutaceaeStem barkMethanol extractDihydroacridineHydroxy-1, 3-dimethoxy-10-methyl-9-acridone (321), 3-hydroxy-1, 5, 6--trimethoxy-9-acridone (322) with MIC of 5.1 and 1.5μg/ml, respectively, against M. tuberculosis H37Rv by MABA[168]Zanthoxylum schinifoliumRutaceaeLeafMethanolic extractsCoumarin7-[(2E) −3,7-dimethylocta-2,6-dienoxy] −8-methoxychromen-2-one (collinin) (323) with MIC50 of 3.13–6.25μg/ml against both drug-susceptible and -resistant strains of M. tuberculosis by luminescent viability assay kit[169]Zanthoxylum wutaienseRutaceaeRootMethanol extractBenzofuran, furo[3,2-b]quinoline7-Methoxyanodendroate (324), 7-methoxywutaifuranal (325), wutaiensal (326), dictamnine (327), andγ-fagarine (328), with MIC of 35, 35, 30, 30, and 30 μg/ml, respectively, against M. Tuberculosis H37Rv by the agar proportion method[170]Zingiber cassumunarZingiberaceaeRootMethanolThree fatty acid esters(E)-4-(3,4-Dimethoxyphenyl)but-3-en-1-yl linoleate (329), (E)-4-(3,4-dimethoxyphenyl)but-3-en-1-yl oleate (330), and (E)-4-(3,4-dimethoxyphenyl) but-3-en-1-yl palmitate (331),with MIC of 200, 100, and 200μg/ml, respectively, against M. tuberculosis H37Ra by MABA[171]Ziziphus cambodianaRhamnaceaeRoot barkAcetate extractTriterpenes3-O-Vanillylceanothic acid (332), betulinaldehyde (333), betulinic acid (334), and 2-O-E-p-coumaryl alphitolic acid (335) with MIC of 25, 25, 25, and 12.5μg/ml, respectively, against M. tuberculosis H37Ra by MABA[172]MABA: microplate alamar blue assay; MIC: minimum inhibitory concentration.Many plants consisted several components with anti-TB activity, and only the active compounds that were reported are listed in this review. Table1 presents the list of 335 compounds, which were tested for their anti-TB activities. Those 335 compounds could be divided into mainly 11 classes, such as terpenes (37 types), ketones (31), acids (14), alcohols (10), esters (9), hydrocarbons (9), quinones (8), furans (7), phenols (6), and quinolones (3). The typical structures of the 335 compounds are sorted out in Figure 2. Of all the anti-TB natural compounds, the derivatives and analogs of phytol, flavones, and terpenoids were critically reviewed by Singh et al. [173] and Cantrell et al. [174] for their pharmacological activities of various diseases. These 335 compounds were natural products or secondary metabolites, and few of their synthetic modified derivatives have been mentioned in this review.Figure 2
Typical structures sorted out of the 335 anti-TB compounds from the reported medicinal plants, which included sesquiterpene, diterpene, triterpene, quinone, polyphenol, fatty alcohol, flavanone, flavonoid, chalcone, benzofuran, fatty acid ester, fatty acid, steroid, amide, and coumarin.In fact, many semisynthetic derivatives proved to be more active than the parent compounds; for example, the methylation of natural compounds of mulinenic acid and 13-hydroxy-mulin-11-en-20-oic acid methyl ester decreased the minimum inhibitory concentration (MIC) by 8 times [42]; n-propyl ester and n-butyl ester of isomulinic acid decreased the MIC by 4 times [42]. The triacetylated methyl gallate decreased the MIC 2-4 times, since the acetylation increased the lipophilic nature of methyl gallate [19]. The abietane diterpenoid had an MIC of 1.2 μg/ml, while its C-12 acetate analogue was more active with an MIC of 0.89 μg/ml [175]. One of the most impressing natural products was (+)-calanolide A, a novel dipyranocoumarin from the Malesian tree Calophyllum lanigerum var. austrocoriaceum. This distinct compound was first reported with good activity against the strains of HIV-1, which was resistant to diverse other nonnucleosides as well as nucleoside (AZT) reverse transcriptase inhibitors [176, 177]. Later, the novel calanolides with the ring-D-modification were synthesized with selective activity against the replication and/or nonreplicating M. tuberculosis by targeting the Rv2466c [55]. In particular, analogues bearing 2-nitrofurano group at the ring D position markedly improved the in vitro efficacy and reduced the mammalian cell toxicity, when compared with the parent compound (+)-calanolide A [55]. Recently, Mu et al. demonstrated that the nitrofuranyl calanolides could be employed as novel fluorescent probes that can serve as a much needed high-throughput and low-cost detection method for detection of living M. tuberculosis and can precisely determine the MIC values for a full range of available drugs [178]. Thus, different modifications of the calanolide derivatives demonstrated three aspects (anti-HIV, anti-TB, and TB diagnosis) of potent usage in TB disease.Of all the 335 natural plant compounds and its semisynthetic analogues, only few were found for their mechanistic role of their anti-TB activities. The calanolides target the Rv2466c, and hyperenone A inhibits the ATP-dependent MurE ligase, which involves in the cytoplasmic steps of peptidoglycan biosynthesis [104]. It was reported that saussureamine C (methyl 3-O-feruloylquinate) targets the folC [151] and eupractenoid B targets the acetyl transfer activity of GlmU [90]. The trans, trans-1, 7-diphenylhepta-4, 6-dien-3-one target the efflux pumps [26]. In silico analysis revealed that some fatty acids could bind at the cleft between the N-terminal and C-terminal lobes of the cytosolic domain of serine/threonine protein kinase B (PknB) [23]. The anti-TB plant medicinal compounds included in this review lack the molecular basis of the action and mechanisms of modulation on the metabolism of M. tuberculosis nor the immunomodulatory activities of those compounds.


## 4. Plants Showing Anti-TB Effect in Form of Crude Extracts

The plants whose active components were isolated and tested for their anti-TB activity as described in Section 3. This section summarizes the reported plants for their anti-TB activity only in the form of crude extracts. They are listed in Table2 with the total amount of 128 plant species. The top five plant families were Asteraceae, Euphorbiaceae, Fabaceae, Piperaceae, and Acanthaceae, and the plant parts mainly used for extraction were root for Fabaceae family and leaf for Asteraceae, Piperaceae, and Acanthaceae, respectively. For Euphorbiaceae family, the plant parts of bark, fruit, leaf, root, and seed were reported with the anti-TB function.Table 2
Medicinal plants and their crude extracts showingin vitro anti-TB activity.
Plant speciesPlant familyPart usedExtractsReferencesAcacia catechuLiliaceaeRootHexane extracts with inhibition of mycobacterial (standard and clinical) growth[179]Acacia senegalFabaceaeRootAqueous extraction has potential antimycobacterial activity[180]Acalypha indicaEuphorbiaceaeLeafAqueous extracts with inhibition of 95% at 4 percentv/v concentration in L-J medium for sensitive M. tuberculosis H37Rv[181]Achyrocline alataAsteraceaeLeaf, stemAqueous extracts againstM. tuberculosis H37Rv strain (ATCC 27294) with MICa of 62.5 μg/ml[182]Acorus calamusAcoraceaeRootAqueous extracts againstM. bovis BCG by OD units[183]Adhatoda vasicaAcanthaceaeLeafMethanol extracts with the oils inhibiting the growth of MTB B19-4 at 2μg/ml[180]Allium sativumLiliaceaeLeafAqueous extract was found to be 63% at 4 percentv/v concentration in L-J medium for sensitive M. tuberculosis H37Rv[181]Aloe veraXanthorrhoeaceaeLeafAqueous extract was found to be 41% at 4 percentv/v concentration in L-J medium for sensitive M. tuberculosis H37Rv[181, 184]Alstonia scholarisApocynaceaeLeafMethanol extracts have potential antimycobacterial activity and the synergistic group consisting of rifampicin in murine model[185]Amborella trichopodaAmborellaceaeFruitMethanol extracts againstM. bovis BCG (strain 11-73 P2) with MIC of 2.5 μg/ml[186]Ambrosia ambrosioidesAsteraceaeAerial partsMethanolic extracts againstM. tuberculosis H37Rv with MIC of 790 μg/ml[187]Ambrosia confertifloraAsteraceaeAerial partsMethanol, chloroform, dichloromethane, and ethyl acetate extracts againstM. tuberculosis H37Rv with MIC of 200, 90, 120, and 160 μg/ml, respectively[187]Amphipterygium simplicifoliumJulianaceaeLeafDichloromethane-methanol extracts (1.1) inhibit theM. tuberculosis H37Rv at 50 μg/ml with 90.5±1.0%[188]Andrographis paniculataAcanthaceaeAerial partsHexane and methanol (1 : 5) extracts with maximum antimycobacterial activity at 250μg/ml against all the tested strains of M. tuberculosis (H37Rv, MDR, and drug sensitive)[189]Andrographis paniculataAcanthaceaeLeafEthanol extracts with inhibition of mycobacterial (standard and clinical) growth[7, 190]Angiopteris evectaMarattiaceaeLeaf80% methanol extract againstM. tuberculosis H37Rv ATCC 25618 with an MIC of 400 μg/ml[191]Apodytes dimidiataIcacinaceaeLeafHexane extractions against the field strain of MDR-TB and against theM. tuberculosis H37Rv with MIC of 0.47 and 0.31 mg/ml, respectively[192]Artemisia ludovicianaAsteraceaeBark, leafHexane extracts against MDR-TB clinical isolates with MIC of 25-100μg/ml[58, 193]Artemisia nilagiricaAsteraceaeLeafEthanol extracts againstM. smegmatis with IC50c of 300 μg/ml[194]Beilschmiedia obscuraLauraceaeRootEthyl acetate extracts againstM. tuberculosis H37Rv with MIC of 31.25 μg/ml by MABAb[195]Bidens odorataAsteraceaeAerial partsHexane, dichloromethane, ethyl acetate, and ethanolic extracts againstM. tuberculosis H37Rv (ATCC 27294) with MIC of 100, 12.5, 12.5, and 12.5 μg/ml[196]Bridelia micranthaEuphorbiaceaeBarkAcetone extracts againstM. tuberculosis H37Ra with MIC of 25 μg/ml[197]Calluna vulgarisEricaceaeAerial partsEthyl acetate extracts with 97% inhibition at 100μg/ml against M. tuberculosis H37Rv (ATCC 27294)[198]Calophyllum brasilienseClusiaceaeLeafDichloromethane-methanol extracts (1.1) inhibit theM. tuberculosis H37Rv at 50 μg/ml with 82.8±0.4%[188]Capparis zeylanicaCapparidaceaeLeafEthyl acetate extracts againstM. tuberculosis H37Rv with the 32 mm minimum zone of inhibition[199, 200]Carya illinoensisJuglandaceaeBarkHexane extracts againstM. tuberculosis H37Rv with MIC of 31 μg/ml[193]Cassia sopheraCaesalpiniaceaeSeedMethanol extracts againstM. smegmatis with MIC of 125 μg/ml[201]Chenopodium ambrosioidesAmaranthaceaeLeaf80% ethanol crude extracts againstM. tuberculosis H37Ra (ATCC 25177™) with MIC of 5000 μg/ml[184]Chrysactinia mexicanaAsteraceaeRootEthyl ether extract against a drug-resistant strain ofM. tuberculosis CIBIN/UMF15:99 with MIC of 62.5 μg/ml[202]Citrullus colocynthisCucurbitaceaeLeafChloroform extracts againstM. tuberculosis H37Rv with MIC of 2.5 mg/ml by MABA[203]Citrus sinensisRutaceaeFruit peelHexane extracts against two drug-resistant strains ofM. tuberculosis with MIC of 25 and 50 μg/ml[204]Cladonia arbusculaCladoniaceaeRootHexane and ethyl acetate extracts with 96% and 99% inhibition at 100μg/ml against M. tuberculosis H37Rv (ATCC 27294), respectively[198]Cocculus hirsutusMenispermaceaeLeafEthanol extracts againstM. tuberculosis H37Rv (ATCC 27294) with MIC of 500 μg/ml[196]Codiaeum peltatumEuphorbiaceaeStemMethanol extracts againstM. bovis BCG (strain 11-73 P2) with MIC of 100 μg/ml[186]Combretum aculeatumCombretaceaeAerial partAqueous extracts inhibitingM. marinum with MIC of 0.2 mg/ml[205]Costus speciosusZingiberaceaeStem, flowerHexane partition from methanol extracts againstM. tuberculosis H37Rv with MIC of 100 μg/ml[206]Cremaspora trifloraRubiaceaeLeafAcetone extracts decreased 16-fold of MIC in combination with fifampicin againstM. aurum and reduction of the MICs of the anti-TB drug ranged from 2-fold to 4-fold, 2-fold to 64-fold, and 2-fold to 64-fold for M. smegmatis, M. aurium, and M. tuberculosis, respectively[207]Croton sylvaticusEuphorbiaceaeLeaf, root, stem barkDecoction, not known[208]Curcuma caesiaZingiberaceaeRhizomeEthanol extract againstM. tuberculosis H37Rv (ATCC 27294) with MIC of 31.25 μg/ml[196]Cymbopogon citratusPoaceaeStem, rhizomeHexane partition from methanol extracts of 200μg/ml against M. tuberculosis H37Rv[206]Cyperus rotundusCyperaceaeRootEthanol extracts againstM. tuberculosis H37Rv (ATCC 27294) with MIC of 62.5 μg/ml[209]Davilla ellipticaDilleniaceaeLeafChloroform extracts showed a promising antimycobacterial activity with a MIC of 62.5μg/ml by MABA[209]Dissotis rotundifoliaMelastomataceaeLeaf80% ethanol crude extracts againstM. tuberculosis H37Ra (ATCC 25177™) with MIC of 5000 μg/ml[184]Dryopteris stewartiiDryopteridaceaeWhole plantDecoction, not known[203]Echinops giganteusAsteraceaeRootMethanol extracts againstM. tuberculosis H37Ra and H37Rv with MIC of 32 and 16 μg/ml, respectively[210]Empetrum nigrumEmpetraceaeRootHexane extracts with 95% inhibition at 100μg/ml against M. tuberculosis H37Rv (ATCC 27294)[198]Erythrina abyssinicaFabaceaeRoot barkMethanol extracts showed the highest activity onM. tuberculosis H37Rv (MIC 390 μg/ml)[211]Eulophia nudaOrchidaceaeTubersEthanol extracts againstM. tuberculosis H37Rv (ATCC 27294) with MIC of 500 μg/ml[196]Euphorbia albomarginataEuphorbiaceaeShootsExtracts by n-hexane, dichloromethane, ethyl acetate, and methanol individually againstM. tuberculosis H37Rv with MIC of 250-1000 μg/ml[212]Euphorbia hirtaEuphorbiaceaeLeafEthyl acetate extracts showed better activity with maximum of 64.73% reduction in relative light units againstM. tuberculosis H37R[213]Evodia elleryanaRutaceaeBarkEthyl acetate extracts with 95% inhibition ofM. tuberculosis H37Ra grown in vitro (ATCC 25177) at 50 μg/ml[214]Ficus surMoraceaeRoot80% ethanol againstM. tuberculosis H37Ra (ATCC 25177) with MICof 0.78 mg/ml[215]Ficus citrifoliaMoraceaeLeaf95% ethanol extracts againstM. tuberculosis H37Rv (ATCC 27294) with 91% inhibition at 100 μg/ml[216]Flourensia cernuaAsteraceaeLeafHexane extracts against sensitive and resistant strains, respectively, with MIC of 25-50μg/ml[217]Foeniculum vulgareUmbelliferaeAerial partsHexane extracts againstM. tuberculosis H37Rv with MIC of 100 μg/ml[204]Globularia alypumGlobulariaceaeLeafPetroleum ether extracts againstM. tuberculosis H37Rv with IC50 of 77 μg/ml[218]Glycyrrhiza glabraFabaceaeRootEthanol extracts againstM. tuberculosis H37Rv (ATCC 27294) with MIC of 250 μg/ml[219]Guaiacum coulteriZygophyllaceaeFlowerMethanol extracts againstM. tuberculosis H37Rv with MIC of 1000 μg/ml[188]Guiera senegalensisCombretaceaeAerial partsAqueous extracts inhibitingM. marinum with MIC of 200 μg/ml[205]Gymnosperma glutinosumAsteraceaeLeafHexane extracts againstM. tuberculosis H37Ra and H37Rv both at 31.2 μg/ml[220]Helianthus annuusAsteraceaeStemExtracts by n-hexane, dichloromethane, ethyl acetate, and methanol individually againstM. tuberculosis H37Rv with MIC of 250-500 μg/ml[212]Heracleum maximumApiaceaeRootAqueous extracts againstM. bovis BCG by OD units[183]Heteromorpha trifoliataApiaceaeLeafEthanol extracts againstM. tuberculosis H37Rv with MIC of 80 μg/ml[221]Hygrophila auriculataAcanthaceaeRoot, leafAcetone extract againstM. tuberculosis H37Rv by y the disc diffusion method[222]Juglans mollisJuglandaceaeBarkHexane extracts againstM. tuberculosis H37Rv with MIC of 50 μg/ml[193]Juglans regiaJuglandaceaeBark, leafHexane extracts againstM. tuberculosis strain H37Rv with MIC of 100 μg/ml[193, 194]Justicia adhatodaAcanthaceaeLeafEthanolic extract againstM. tuberculosis H37Rv by y the disc diffusion method[223]Khaya senegalensisMeliaceaeBark, leafEthanolic extracts againstM. tuberculosis H37Ra with MIC of 6.25 μg/ml[224]Lantana camaraVerbenaceaeLeafMethanol extracts againstM. tuberculosis H37Rv with MIC of 20 μg/ml[17]Lantana hispidaVerbenaceaeLeafHexane extracts against drug-resistant clinical isolates ofM. tuberculosis with MIC of 100-200 μg/ml[193, 194]Laurelia novae-zelandiaeMonimiaceaeLeaf, flowerAqueous extract againstM. smegmatis with IC50 of 0.02 mg/ml[225]Leucophyllum frutescensScrophulariaceaeRoot, leafMethanol extracts against a drug-resistant strain ofM. tuberculosis CIBIN/UMF15:99 with MIC of 62.5 μg/ml[202]Maerua edulisCapparaceaeRootHexane extracts againstM. bovis BCG, M. tuberculosis H37Ra with MIC 31.2–62.5 μg/ml[226]Mallotus philippensisEuphorbiaceaeLeaf, fruitEthanolic extracts of fruit and leaves againstM. tuberculosis H37Rv (ATCC 27294) both with MIC of 250 μg/ml[227]Metrosideros excelsaMyrtaceaeLeafMethanol extracts againstM. smegmatis with IC50 of 0.11 mg/ml[226]Millettia stuhlmanniiFabaceaeLeafAcetone extracts againstM. smegmatis with MIC of 0.13 mg/ml[228]Morinda citrifoliaRubiaceaeLeafAqueous extract has an inhibition rate of 89% againstM. tuberculosis H37Rv[180]Mucuna imbricataFabaceaeSeedMethanol extracts have potential antimycobacterial activity and the synergistic group consisting of rifampicin in murine model[185]Murraya koenigiiRutaceaeLeafEthanol extracts against M. smegmatis with IC50 of 300 μg/ml[194]Musa acuminataMusaceaeStemMethanol extracts against drug-resistant variants ofM. tuberculosis with MIC of 200 μg/ml[204]Myoporum crassifoliumScrophulariaceaeWoodHydrodistillation with essential oils againstM. bovis BCG (strain 11-73 P2) with MIC of 50 μg/ml[186]Myrica galeMyricaceaeRoot, stemEthyl acetate extracts with 96% inhibition at 100μg/ml against M. tuberculosis H37Rv (ATCC 27294)[198]Myristica fatuaMyricaceaeAlmondDichloromethane soluble extracts againstM. bovis BCG (strain 11-73 P2) with MIC of 50 μg/ml[186]Nasturtium officinaleCruciferaeAerial partsChloroform extracts against two drug-resistant strains ofM. tuberculosis with MIC of 50-100 μM[204]Olea europaeaOleaceaeLeafHexane extracts against the drug-resistant variants ofM. tuberculosis with MIC of 25-100 μM[204]Otostegia integrifoliaLamiaceaeRootChloroform extract of roots was the most active onM. tuberculosis H37Rv (MIC 156 μg/ml) and AOZ8W-4 (MDR-TB clinical isolate) (MIC 0.078 mg/ml)[229]Pelargonium graveolensGeraniaceaeSeedHydrodistillation for essential oil against tested isolates ranged from 19.5μg/ml to 78 μg/ml[230]Pelargonium sidoidesGeraniaceaeRootAqueous extracts inhibiting the growth ofM. tuberculosis H37Rv (ATCC 27294) by 96% at a sample concentration of 12.5 μg/ml[231]Pentanisia prunelloidesRubiaceaeRoot80% ethanol againstM. tuberculosis H37Ra (ATCC 25177) with MICof 0.78 mg/ml[215]Persea americanaLauraceaeLeaf, seedMethanolic extracts againstM. tuberculosis H37Ra with MIC of 31.2 μg/ml and H37Rv; chloroformic extract of seeds against M. tuberculosis H37Rv MIC less than 50 μg/ml[229, 232]Phymaspermum acerosumAsteraceaeRoot, leafEthanol and water extracts had the best MIC value of 20μg/ml against five M. tuberculosis strains[221]Piper cernuumPiperaceaeLeafHydrodistillation with water displayed moderate activity against theM. tuberculosis H37Rv with MIC of 125 μg/ml[233]Piper diospyrifoliumPiperaceaeLeafHydrodistillation with water displayed moderate activity against theM. tuberculosis H37Rv with MIC of 125 μg/ml[233]Piper guineensePiperaceaeSeedMethanol extracts againstM. tuberculosis H37Ra and H37Rv with MIC of 256 μg/ml[210]Piper imperialePiperaceaeFlowerEthanolic extracts againstM. tuberculosis H37Rv with MIC of 75 μg/ml[234]Piper rivinoidesPiperaceaeLeafHydrodistillation with water displayed moderate activity against theM. tuberculosis H37Rv with MIC of 125 μg/ml[233]Piper sarmentosumPiperaceaeLeafExtracts with petroleum ether, chloroform, and methanol, againstM. tuberculosis H37Rv with MIC of 25, 25, and 12.5 μg/ml[235]Pisonia borinquenaNyctaginaceaeLeaf95% ethanol extracts againstM. tuberculosis H37Rv (ATCC 27294) with 85% inhibition at 100 μg/ml[216]Pittosporum tenuifoliumPittosporaceaeLeafEthanol extracts againstM. smegmatis with IC50 of 0.78 mg/ml[225]Pluchea indicaAsteraceaeFlower and leaf80% methanol extract againstM. tuberculosis H37Rv ATCC 25618 with an MIC of 800 μg/ml[191]Plumbago zeylanicaPlumbaginaceaeRootEthanol extract againstM. tuberculosis H37Rv (ATCC 27294) with MIC of 31.25 μg/ml[196]Psychotria zombamontanaRubiaceaeLeafAcetone extract decreased 256-fold of MIC in combination with fifampicin againstM. aurum and reduction of the MICs of the anti-TB drug ranged from 2-fold to 4-fold, 2-fold to 64-fold, and 2-fold to 64-fold for M. smegmatis, M. aurium, and M. tuberculosis, respectively[207]Pterocarpus osunFabaceae (Leguminosae)StemChloroform extract againstM. tuberculosis H37Rv and M. bovis BCG with MIC of 1225 μg/ml and 1100 μg/ml, respectively, by MABA[67, 236]Pterolobium stellatumFabaceaeRootChloroform extracts of roots were the most active onM. tuberculosis H37Rv (MIC 39 μg/ml) and AOZ8W-4 (MDR-TB clinical isolate) (MIC 0.078 mg/ml)[229]Rhynchosia precatoriaFabaceaeRootExtracts by n-hexane, dichloromethane, ethyl acetate, and methanol individually againstM. tuberculosis H37Rv with MIC of 15.6-125 μg/ml[212]Ricinus communisEuphorbiaceaeSeedHexane extracts againstM. tuberculosis H37Rv sensitive strain with MIC of 2.5 mg/ml by MABA[203]Rosmarinus officinalisLamiaceaeLeafEthanolic extracts againstM. tuberculosis H37Ra with MIC of 6.25 μg/ml[224]Satureja aintabensisLamiaceaeAerial partsExtraction with petroleum ether, ethyl acetate, and methanol killedM. tuberculosis with MIC of 50-800 μg/ml[237]Satyrium nepalenseOrchidaceaeFlowerHexane extracts againstM. tuberculosis H37Rv TMC-102 with MIC of 15.7 μg/ml[238]Schinus molleAnacardiaceaeFruitMethanol extract against a drug-resistant strain ofM. tuberculosis CIBIN/UMF15:99 with MIC of 125 μg/ml[202]Securidaca longepedunculataPolygalaceaeRootHexane extracts againstM. bovis BCG, M. tuberculosis H37Ra, and H37Rv with 62.5 μg/ml[226]Solanum torvumSolanaceaeLeaf80% ethanol crude extracts againstM. tuberculosis H37Ra (ATCC 25177™) with MIC of 156.3 μg/ml[184]Sphaeranthus indicusAsteraceaeFloral headEthanol extract againstM. tuberculosis H37Rv (ATCC 27294) with MIC of 31.25 μg/ml[196]Sterculia setigeraSterculiaceaeLeafHexane, dichloromethane, and ethyl acetate extracts againstM. tuberculosis H37Rv with MICs of 84 μg/ml, 62 μg/ml, and 128 μg/ml, respectively[239]Swinglea glutinosaRutaceaeFruit peelAqueous extracts for essential oils againstM. tuberculosis H37Rv (ATCC 27294) with MIC of 100 μg/ml[182]Tabernaemontana elegansApocynaceaeRootEthyl acetate extracts againstM. tuberculosis H37Rv with MIC of 15.6 μg/ml[226]Tabernaemontana coronariaApocynaceaeLeafHexane partition from methanol extracts of MIC of 100μg/ml against M. tuberculosis H37Rv[206]Terminalia phanerophlebiaCombretaceaeLeaf, root, twig80% ethanol againstM. tuberculosis H37Ra (ATCC 25177) with 0.30 and 0.78 mg/ml, respectively[215]Terminalia sericeaCombretaceaeStem barkAcetone extracts againstM. tuberculosis H37Ra with MIC of 25 μg/ml[197]Thymus sibthorpiiLamiaceaeAerial partsExtracts with petroleum ether, ethyl acetate, and methanol againstM. tuberculosis with MIC of 50–800 μg/ml[237]Trachyspermum copticumApiaceaeAerial partsHydrodistillation extracts againstM. kansasii and MDR-TB with MICs of 78 μg/ml[230]Urtica dioicaUrticaceaeLeafHexane extracts againstM. smegmatis with MIC of 250 μg/ml[201]Uvaria rufaAnnonaceaeLeafLead acetate-treated crude chloroform extracts againstM. tuberculosis H37Rv with MIC of 8 μg/ml[136]Vetiveria zizanioidesPoaceaeRootEthanolic extract and hexane fraction 500μg/ml or 50 μg/ml against M. tuberculosis H37Rv and H37Ra[240]Vismia bacciferaClusiaceaeLeafDichloromethane-methanol extracts (1.1) inhibit theM. tuberculosis H37Rv at 50 μg/ml with 70.3±0.5%[188]Xylopia aethiopicaAnnonaceaeFruit, barkMethanol extracts againstM. tuberculosis H37Ra and H37Rv with MIC of 512 μg/ml[210]Zanthoxylum capenseRutaceaeRootDichloromethane extracts againstM. bovis BCG, M. tuberculosis H37Ra, and H37Rv with MICs of 31.2 μg/ml[226]Zingiber officinaleZingiberaceaeRhizomeEthanol extract againstM. tuberculosis H37Ra with MIC of 2500 μg/ml by MABA[184]aMinimum inhibitory concentration (MIC); bmicroplate alamar blue assay (MABA); chalf maximal inhibitory concentration (C50).Among the extraction methods, ethanol, hexane, and methanol were found to be the top three frequently used extracting solvents, while chloroform, dichloromethane, acetone, and ethyl acetate were used to a lesser extent. Of course, aqueous extract method was also popularly used, which involved the process of soaking, boiling, or/and hydrodistilling. Although the plant part used for study does not determine the extraction method, as a general rule, low molecule organic solvents are recommended when there is no reference.To date, no specific cut-off value has been established as a reference to analyze the anti-TB activity results of the plant extracts, and many different methods are available to evaluate the activity. As of date, only a few anti-TB plant extracts in Table2 have been tested in preclinical or clinical trials. It is encouraging that more and more promising crude extracts are now paving a way for the clinical test for their therapeutic applications. This section can provide a new perspective in expanding the anti-TB plant species for the development of anti-TB medicine in the future.


## 5. Medicinal Plants Only Found in Formula Prescribed by the Traditional Healers

Traditional healers continually serve the public health in most of the countries. Some ethnomedical information has been published based on many plant species in anti-TB formulas documented by different traditional healing systems, ranging from the poor documented oral African medicine to the well-documented Ayurveda or Chinese medicine. These reports inspired the scientists to find more effective compounds for tuberculosis. The investigations of medicinal plants using frontier technologies are now being reconsidered to be a feasible approach for discovering novel bioactive compounds and crude extracts, in order to solve the wide spreaded TB problems. Table3 shows the main species or families of the traditional plant medicines and their botanical details in the published papers by the systemic survey of the prescribed formula, but very few studies reveal the working compounds or active crude extracts.Table 3
Important anti-TB traditional medicinal plants in literature by the systemic survey on the prescribed formula.
Species numberFamily numberMain familiesCountry or regionReferences1310Asteraceae (3), Chrysobalanaceae, Araliaceae, Acanthaceae, Chrysobalanaceae, Cucurbitaceae, Fabaceae, Lamiaceae, Melastomataceae, Phyllanthaceae, PolygonaceaeBurundian[241]98Apocynaceae, Verbenaceae, Rubiaceae, Goodeniaceae, Agavaceae, Moraceae, Myrtaceae, ZingiberaceaeManus Province, Papua New Guinea[242]18477Fabaceae (21), Asteraceae (12), Malvaceae (11)Bapedi (South Africa)[243]3021Alliaceae (3), Rutaceaeare (3), Apiaceae (2), Caryophyllaceae (2), Asteraceae (2), Lamiaceae (2), Myrtaceae (2), Solanaceae (2)Nkonkobe municipality, Eastern Cape Province (South Africa)[244]2112Asteraceae, Fabaceae, GeraniaceaeMangaung metro, Thabo Mofutsanyana, and Lejweleputswa in South Africa[245]2514Fabaceae (5), Euphorbiaceae (3), Asteraceae (3), Lamiaceae (12%)Bas-Congo Province, Democratic Republic of Congo[208]1513Amaryllidaceae (3), Xanthorrhoeaceae (2), Arecaceae (2), Solanaceae (2), Meliaceae, Acanthaceae, Poaceae, Phyllanthaceae, Melastomataceae, Poaceae, Cyperaceae, Zingiberaceae, Amaranthaceae, AsteraceaeGreater Accra and eastern communities in Ghana[246]9548Loranthaceae (6), Caesalpiniaceae (5), Papilionaceae (5), Poaceae (4), Mimosaceae (4), Scrophulariaceae (4), Anacardiaceae (3), Combretaceae (3), Liliaceae (3), and Solanaceae (3)Niger state, Nigeria[247]6635Rutaceae (7), Euphorbiaceae (5), Rubiaceae (4), Anacardiaceae (3), Fabaceae (3), Verbenaceae (3), Arecaceae (2), Annonaceae (2), Solanaceae (2), Moraceae (2), Rhamnaceae (2)Lao PDR[248]2320Arecaceae (2), Aristolochiaceae (2), Rubiaceae (2)Malaysia[249]18167Asteraceae (31), Fabaceae (14), Lamiaceae (9), Euphorbiaceae (7), Celastraceae (5)South Africa[250]6238Asteraceae (12), Aristolochiaceae (3), Compositae (3), Rosaceae (3), Juglandaceae (2), Zygophyllaceae (2), Verbenaceae (2), Rutaceae (2), Papaveraceae (2), Fabaceae (2)Mexico[10]8836Lamiaceae (9), Asteraceae (7), Papilionaceae (4), Acanthaceae (3), Caesalpiniaceae (3), Capparaceae (3), Euphorbiaceae (3), Mimosaceae (3)Districts of Kamuli, Kisoro, and Nakapiripirit in Uganda[251]9044Fabaceae (13), Asteraceae (7), Moraceae (5), Rutaceae (4)Districts of Mpigi and Butambala, Uganda[252]3522Fabaceae (5), Rutaceae (4), Apocynaceae (3), Menispermaceae (3), Malvaceae (3)Madhya Pradesh, India[196]13245Annonaceae (14), Zingiberaceae (12), Rutaceae (10), Annonaceae (10), Asteraceae (8), Euphorbiaceae (8), Fabaceae (7)Southeast Asian[253]108Fabaceae (3), Canellaceae (1), Rubiaceae (1), Anacardiaceae (1), Rutaceae (1), Myrtaceae (1), Merlucciidae (1), Guttiferae (1)Lake Victoria Basin (Uganda, Kenya, and Tanzania)[254]148Euphorbiaceae (4), Verbenaceae (3), Rutaceae (2)Lake Victoria region and the Samburu community[255]22Achillea millefolium (1), Dryopteris stewartii (1)Kel village, Neelum Valley, Azad Kashmir, Pakistan[256]43Amaryllidaceae (1), Lauraceae (1), Amaranthaceae (1), Asteraceae (1)Sulaymaniyah Province, Kurdistan, Iraq[257]2218Liliaceae (3), Euphorbiaceae (2), Verbenaceae (2)India[258]66Vitaceae (1), Poaceae (1), Pinaceae (1), Musaceae (1), Rosaceae (1), Leguminosae (1)Arabian Peninsula[259]22Asteraceae (1), Dryopteridaceae (1)Pakistan[251]7044Arecaceae (4), Euphorbiaceae (4), Fabaceae (3), Piperaceae (3), Rutaceae (3)Malaysia[191]5626Ranunculaceae (8), Liliaceae (6), Asteraceae (5), Umbellifera (4), Campanulaceae (3), Rubiaceae (4), Rosaceae (2), Scrophulariaceae (2), Labiatae (2), Fabaceae (2)China[260]8230Combretaceae (13), Fabaceae (12), Moraceae (6), Rubiaceae (5), Polygalaceae (5)Nigeria[261]The anti-TB formulas were investigated in many countries or regions, such as China, India, Mexico, South Africa, Pakistan, Iraq, Malaysia, Congo, Lao PDR, Nigeria, Nigeria, Burundi, Papua New Guinea, Lake Victoria Basin (Uganda, Kenya, and Tanzania), Arabian Peninsula, Southeast Asian, and Manus Province. Most anti-TB formulas were found during the ethnopharmacological investigation of the indigenous plants. To strengthen the anti-TB purpose, the present review summarized the anti-TB plant in the formula from the ethnopharmacological publications, with an emphasis on their classification (Table3). Although three reports in Table 3 did not show the botanical family of the anti-TB medical plants in detail, it still can be speculated that the family Fabaceae is the most represented species, followed by Asteraceae, Euphorbiaceae, and Liliaceae families.We need to be aware that the plant medicine used by the traditional healers is based on their according ethnomedical traditional medical theories. In comparison with the western system of medicine, the traditional plant medicines showed certain drawbacks. An important issue of all was that the active components of the herbal drugs prescribed were unknown. The activity of the traditional herbal drugs prescribed by the traditional healers can be greatly affected by the difference in the processing methods, variation in the potency due to difference in plant species and subspecies, varying geographical location of growth, nonuniform quality control standards, etc. Furthermore, for a given plant, a specific place, part, method, and time for collection can significantly affect the therapeutic efficacy [16, 40]. Hence, the plant medicine used by the traditional healers needs a critical evaluation to find the active components.


## 6. Need for Future Research

Although this review presents a big list of plants with effective anti-TB activities from different traditional medicine systems, there is a need of better therapeutic drug monitoring systems and high throughputin vitro assays for the routine screening to identify potentially serious and clinically significant herb-drug interactions [262]. Furthermore, there is a lack of in vivo information regarding the drug metabolism associated interactions with reference to the traditional medicines and the treatment of TB. This requires health care practitioners to ensure a clear communication with patients regarding the possible negative impacts of simultaneous use of certain TMs and prescribed drugs. It was reported that the widely used Sutherlandia frutescens in the treatment of TB in countries of Southern African Development Community interfered with the isoniazid therapy, but the mechanism of this interaction was not clear [263, 264]. Coadministration also resulted in the reduced bioavailability of ofloxacin [265], while piperine showed the ability to increase the bioavailability of the antituberculosis drug rifampicin [266–268].Several issues affect the anti-TB activity of the components of the medicinal plants, such as the variation in the potency due to difference in species, absence of an integrated coding for every species used commonly in TMs, varying geographical location of growth and incorrect identification of drugs, and nonuniform quality control standards [269]. No clinic trial was reported on the crude extracts, and even the pure compounds from the medical plants still need to be elucidated for their constituent characterization and the mechanism of action. Till date, not many compounds have been originated from plants for further modification for use in clinic. We hope that this review will help to find a possible way to get better anti-TB results by making a combination of the compounds originated from plants based on the different TB-killing mechanisms.



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