Ethnobotany, ethnopharmacology, and phytochemistry of traditional medicinal plants used in the management of symptoms of tuberculosis in East Africa: a systematic review

samuel obakiro; Timothy Omara

Objective Many studies on the treatment of tuberculosis (TB) using herbal medicines have been undertaken in recent decades in East Africa. The details, however, are highly fragmented. The purpose of this study was to provide a comprehensive overview of the reported medicinal plants used to manage TB symptoms, and to analyze scientific reports on their effectiveness and safety. Method A comprehensive literature search was performed in the major electronic databases regarding medicinal plants used in the management of TB in East Africa. A total of 44 reports were retrieved, and data were collected on various aspects of the medicinal plants such as botanical name, family, local names, part(s) used, method of preparation, efficacy, toxicity, and phytochemistry. The data were summarized into percentages and frequencies which were presented as tables and graphs. Results A total of 195 species of plants belonging to 68 families and 144 genera were identified. Most encountered species were from Fabaceae (42.6%), Lamiaceae (19.1%), Asteraceae (16.2%), and Euphorbiaceae (14.7%) families. Only 36 medicinal plants (18.5%) have been screened for antimycobacterial activity. Out of these, 31 (86.1%) were reported to be bioactive with minimum inhibitory concentrations ranging from 47 to 12,500 μg/ml. Most tested plant extracts were found to have acceptable acute toxicity profiles with cytotoxic concentrations on normal mammalian cells greater than 200 μg/ml. The most commonly reported phytochemicals were flavonoids, terpenoids, alkaloids, saponins, cardiac glycosides, and phenols. Only Tetradenia riparia, Warburgia ugandensis, and Zanthoxylum leprieurii have further undergone isolation and characterization of the pure bioactive compounds. Conclusion East Africa has a rich diversity of medicinal plants that have been reported to be effective in the management of symptoms of TB. More validation studies are required to promote the discovery of antimycobacterial drugs and to provide evidence for standardization of herbal medicine use.

Obakiro et al. Tropical Medicine and Health https://doi.org/10.1186/s41182-020-00256-1 (2020) 48:68 Tropical Medicine and Health REVIEW Open Access Ethnobotany, ethnopharmacology, and phytochemistry of traditional medicinal plants used in the management of symptoms of tuberculosis in East Africa: a systematic review Samuel Baker Obakiro1,2,3* , Ambrose Kiprop2,3 , Isaac Kowino3,4, Elizabeth Kigondu5, Mark Peter Odero2,3 , Timothy Omara2,3,6 and Lydia Bunalema7 Abstract Objective: Many studies on the treatment of tuberculosis (TB) using herbal medicines have been undertaken in recent decades in East Africa. The details, however, are highly fragmented. The purpose of this study was to provide a comprehensive overview of the reported medicinal plants used to manage TB symptoms, and to analyze scientific reports on their effectiveness and safety. Method: A comprehensive literature search was performed in the major electronic databases regarding medicinal plants used in the management of TB in East Africa. A total of 44 reports were retrieved, and data were collected on various aspects of the medicinal plants such as botanical name, family, local names, part(s) used, method of preparation, efficacy, toxicity, and phytochemistry. The data were summarized into percentages and frequencies which were presented as tables and graphs. Results: A total of 195 species of plants belonging to 68 families and 144 genera were identified. Most encountered species were from Fabaceae (42.6%), Lamiaceae (19.1%), Asteraceae (16.2%), and Euphorbiaceae (14.7%) families. Only 36 medicinal plants (18.5%) have been screened for antimycobacterial activity. Out of these, 31 (86.1%) were reported to be bioactive with minimum inhibitory concentrations ranging from 47 to 12,500 μg/ml. Most tested plant extracts were found to have acceptable acute toxicity profiles with cytotoxic concentrations on normal mammalian cells greater than 200 μg/ml. The most commonly reported phytochemicals were flavonoids, terpenoids, alkaloids, saponins, cardiac glycosides, and phenols. Only Tetradenia riparia, Warburgia ugandensis, and Zanthoxylum leprieurii have further undergone isolation and characterization of the pure bioactive compounds. (Continued on next page) * Correspondence: sobakiro@gmail.com 1 Department of Pharmacology and Therapeutics, Faculty of Health Sciences, Busitema University, P.O. Box 1460, Mbale, Uganda 2 Department of Chemistry and Biochemistry, School of Sciences and Aerospace Studies, Moi University, P.O. Box 3900-30100, Eldoret, Kenya Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Obakiro et al. Tropical Medicine and Health Page 2 of 21 (2020) 48:68 (Continued from previous page) Conclusion: East Africa has a rich diversity of medicinal plants that have been reported to be effective in the management of symptoms of TB. More validation studies are required to promote the discovery of antimycobacterial drugs and to provide evidence for standardization of herbal medicine use. Keywords: Antimycobacterial, Antitubercular, Medicinal plants, Herbal medicine, Phytochemicals, Mycobacterium tuberculosis Background Tuberculosis (TB) is a chronic infectious bacterial disease caused by Mycobacterium tuberculosis (Mtb). It affects mainly the respiratory system but may also affect other organs of the body causing pulmonary and extrapulmonary TB respectively. The World Health Organization (WHO) estimated that a quarter of the world’s population is infected with Mtb and thus at a risk of developing TB [1]. Although TB affects all people, those living with HIV/AIDS are at a higher risk of developing active TB [2]. The burden of TB is still high as it is ranked among the ten diseases of global concern [3]. In 2018, a total of 10 million new cases and 1.49 million deaths due to TB were reported worldwide. In East Africa, 378,000 new cases and 91,000 deaths (24%) occurred. In East Africa, Kenya and Tanzania are still ranked among the 30 countries with a high burden of TB in the world [1]. Treatment of TB remains a challenge due to the emergence of multidrug-resistant Mtb strains and extensively drug-resistant TB cases which poorly respond to the first line antitubercular drugs (rifampicin, isoniazid, pyrazinamide, and ethambutol). These drugs also have side effects and a high potential to interact with antiretroviral drugs resulting in increased toxicity, poor compliance, and treatment failure [4–6]. As a result, many TB patients have resorted to using alternative and complementary medicines with herbal remedies being the most widely used in the management of tuberculosis [7]. Due to limited access to health services and chronic poverty in East Africa, many people not only believe that herbal medicines are efficacious and safe but also affordable, available, and culturally acceptable [8–10]. Thus, there is widespread use of herbal remedies by many people in the East Africa to manage symptoms of TB [7–13]. The WHO also reported that approximately 60% of the world’s population depend on non-conventional therapies for primary health care [14]. The search to discover new effective drugs against Mtb has intensified globally in the last decade as the current therapies become less effective and in an attempt to have a world free of TB by 2035 [1]. With natural products being the leading sources of novel drugs, ethnobotanical surveys and scientific validation studies have been conducted on East African flora in the past decades [7–10]. Several plant species have been documented and some of their extracts, fractions, and isolated pure compounds have been tested for efficacy and safety [15–18]. However, this information is highly fragmented. Comprehensive data on medicinal plants used in the management of TB is important for the conservation of these species as some of them are either rare or endangered. It also provides more evidence that increases the confidence in the utilization of these herbal remedies for primary health care as well as their regulation by relevant authorities in case of ineffectiveness and toxicity [19, 20]. The analysis and synthesis of the results may also help in identifying existing gaps and challenges in the current research and stimulates future research opportunities. This can lead to identification of novel molecules that can be developed into new antitubercular drugs with better efficacy and safety profiles [21]. This review was therefore undertaken to compile a comprehensive report on the ethnobotany, ethnopharmacology, and phytochemistry of medicinal plants used in management of symptoms of TB in the East African region so as to generate knowledge on the current status and future opportunities for drug discovery against TB. Methods Reporting and protocol registration This systematic review was reported according to the Preferred Reporting Items for the Systematic Reviews and Meta-Analyses (PRISMA) guidelines [22]. The protocol used in this study was registered with the International Prospective Register of Systematic Reviews (PROSPERO) and can be accessed at their website (https://www.crd.york.ac.uk/prospero/display_record. php?RecordID=187098) with the registration number CRD42020187098. Literature search strategy Relevant literature pertaining the ethnobotany, phytochemistry, efficacy and safety of medicinal plants utilized in management of symptoms of TB in Uganda, Kenya, Tanzania, Rwanda, Burundi and South Sudan were re- Obakiro et al. Tropical Medicine and Health Page 3 of 21 (2020) 48:68 trieved from Scopus, Web of Science Core Collection, PubMed, Science Direct and Google Scholar [23–25]. Key search words such as tuberculosis, mycobacteria, tuberculosis symptoms, tuberculosis treatment, vegetal, antituberculosis, antitubercular, antimycobacterial, cough, traditional medicine, ethnobotany, alternative medicine, and ethnopharmacology combined with either Uganda, Kenya, Tanzania, Rwanda, Burundi, or South Sudan were used. All publishing years were considered, and reports in the returned results were carefully scrutinized. More searches were carried out at the Google search engine using more general search terms, such as mycobacteria, tuberculosis, antituberculosis, antimycobacterial, cough, vegetal species, vegetal extract, traditional medicine, alternative medicine, plants, plant extract, vegetal, herbal, complementary therapy, natural medicine, ethnopharmacology, ethnobotany, herbal medicine, herb, herbs, decoction, infusion, macerate, and concoction combined with either Uganda, Kenya, Tanzania, Rwanda, Burundi, or South Sudan. The searches were done independently by the authors for each country and the outputs were saved where possible on databases and the authors received notifications of any new searches meeting the search criteria from Science Direct, Scopus, and Google scholar. Inclusion and exclusion criteria Only full-text original research articles published in peer-reviewed journals, books, theses, dissertations, patents, and conference papers on plants used in the management of symptoms of TB in Uganda, Kenya, Tanzania, Rwanda, Burundi, and South Sudan written in English and dated until April 2020 were considered. Study selection At first, literature screening of the extracted articles involved examining the titles and abstracts for relevant articles for inclusion. This was conducted independently by 6 authors. Then, the full-text articles were evaluated against the inclusion/exclusion criteria. The article selection process resulted in 44 studies included in this systematic review (Figure S1). Data collection A data collection tool was designed in Microsoft Excel (Microsoft Corporation, USA) to capture data on different aspects of medicinal plant species used in TB management. These included botanical name, plant family, local name(s), part(s) used, growth habit, mode of preparation and administration, method of extraction, efficacy, toxicity and phytochemical screening of crude extracts, isolated pure compounds, and efficacy and toxicity. Careful review of the articles was done, and data were captured using the tool. The collected data were checked for completeness, processed independently for each country by the authors and later analyzed. Data analysis Missing information in some studies (local names and growth habit of the plants), and misspelled botanical names were retrieved from the Google search engine and botanical databases (The Plant List, International Plant Names Index, NCBI taxonomy browser, and Tropicos) respectively. Descriptive statistical methods were used to analyze the collected data. Results were expressed as ranges, percentages, and frequencies and subsequently presented as tables and charts. The analyses were performed using SPSS statistical software (Version 20, IBM Inc.) Results and discussion Ethnobotanical studies With the current antitubercular drugs becoming less effective in the management of multidrug-resistant Mtb strains, medicinal plants can provide the novel molecules for development of new efficacious and safe drugs [26, 27]. From the electronic survey in multidisciplinary databases, 44 reports on medicinal plants used for management of symptoms of TB in East Africa were retrieved. A total of 195 species of plants belonging to 68 families and 144 genera were identified (Table 1). Some of these documented plant species have also been reported in other regions across the world for management of TB. For example, Psidium guajava, Catha edulis, Carica papaya, Citrus limon, Lantana camara, Aloe vera, Biden pilosa, Piliostigma thonningii, Tamarindus indica, Ficus platyphyla, and Vernonia cinereal in Nigeria, South Africa, Ethiopia, India, and Mexico [60–64]. This implies that plants continue to occupy a critical niche in the environment due to their rich possession of secondary metabolites (phytochemicals) that have potential to be used as medicines for several ailments that affect man. Therefore, the use of herbal medicines in the provision of primary health care remains an integral component of all health systems globally [14]. Most encountered species were from the family Fabaceae (42.6%), Lamiaceae (19.1%), Asteraceae (16.2%), Euphorbiaceae (14.7%), Moraceae (10.3%), Rubiaceae (10.3%), Rutaceae (8.8%), Burseraceae (7.4%), and Cucurbitaceae (7.4%) (Fig. 1). Fabaceae, Asteraceae, and Lamiaceae were also reported to provide the largest number of plants species used for TB management in South Africa, Ghana, Nigeria, Ethiopia, and India [64–72]. From these families, 15 species were the most cited in East Africa (Fig. 2). These families were reported from at least four countries of East Africa. This could probably be attributed to the abundant distribution of the analogue active substances among species from these families [23, 24]. The family Fabaceae has biosynthetic Obakiro et al. Tropical Medicine and Health Page 4 of 21 (2020) 48:68 Table 1 Medicinal plants used in treatment of symptoms of TB in East Africa Botanical name Family Local Names Habit Part used Country Author (s) Acacia ataxacantha DC Fabaceae Not reported Tree Roots Kenya [28] Acacia hockii De Wild. Fabaceae Kasana (Luganda), Kashiono Tree Leaves, Stem bark Uganda [7, 10] Acacia horrida (L.) Fabaceae Lerai (Samburu) Tree Stem bark Kenya [29] Acacia mearnsii De Wild. Fabaceae Burikoti Tree Stem bark Uganda [10] Acacia nilotica (L.) Willd. Ex Delile Fabaceae Sunut Tree Fruit South Sudan [30] Acacia polyacantha Willd. Fabaceae Egirigirioi Tree Stem bark Uganda [10] Acacia senegal Fabaceae Lderekesi (Samburu) Tree Stem bark Kenya [29] Acacia spectabilis A. Cunn. Ex Benth. Fabaceae Gasiya (Luganda) Tree Leaves Uganda [7] Acanthus pubescens (Thomson ex Oliv.) Engl. Acanthaceae Matovu, Itojo Herb Roots Uganda, Kenya [10, 12] Achyranthes aspera L. Amaranthaceae Muhurura Herb Flower Uganda [10] Achyrospermum carvalhoi Gürke Lamiaceae Kanyamafundo Shrub Leaves Uganda [10] Acokanthera friesiorum Apocynaceae Chipilikwa (Samburu) Tree Leaves Kenya [29] Adenia gummifera Passifloraceae Chepnyalildet (Nandi) Climber Roots Kenya [31] Adhatoda engleriana Lindau C.B. Clarke Acanthaceae Iringoringo (Chagga) Herb Tanzania [32] Roots Ageratum conyzoides L. Asteraceae Namirembe (Luganda) Herb Whole plant Uganda [7] Alangium chinense (Lour.) Harms Omusiisa (Luganda) Herb Stem bark Uganda [7] Cornaceae Albizia anthelmitica Fabaceaa Lamurtana (Samburu) Tree Stem bark Kenya [29] Albizia coriaria Welw. Ex Oliv Fabaceae Mugavu (Luganda), Etek (Lango), Musita (Lusoga), Omusesa (Runyangkore), Omubele (Wanga) Tree Stem bark Uganda, Kenya [7–10, 12, 33] Albizia species Fabaceae Ennongo (Luganda) Tree Stem bark Uganda [7] Albizia versicola Fabaceae Not reported Tree Leaves Tanzania, Kenya [12] Albizia zygia (DC.) Macbr. Fabaceae Ekegonchori (Kuria) Tree Roots Kenya [12] Allium sativum L. Alliaceae Kitungu saumu (Luo), Garlic (Luganda) Herb Leaves Uganda, Kenya [10, 12] Aloe vera (L.) Burm. f. Asphodelaceae Kigaji (Luganda) Herb Leaves Uganda [7] Aloe secundiflora Engl. Aloaceae Sukuroi (Samburu), Osukuroi (Masai), Kiluma (Kamba) Herb Leaves Kenya [12, 34] Amaranthus spinosus Amaranthaceae Kidodo (Luganda) Herb Leaves Uganda [10] Anogeissus leiocarpus (DC.) Guill. & Perr. Combretaceae Sahab Tree Stem bark South Sudan [30, 35] Antiaris toxicaria Lesch. Moraceae Kirundu (Luganda) Tree Stem bark Uganda [7] Asparagus africanus Lam. Asparagaceae Mukira gwango (Luganda) Climber Stem bark Uganda [10] Aspilia africana (Pers.) C.D. Adams Asteraceae Makaayi (Luganda) Emaruoit Herb Root bark, Leaves Uganda [7, 10] Aspilia pluriseta Schweinf. Asteraceae Rirangera Herb Roots Kenya [28] Azadirachta indica L. Meliaceae Muarubaini (Kamba) Tree Seeds Kenya [12] Azadirachta indica A. Juss. Meliaceae Neem tree (Luganda) Tree Leaves, stem bark Uganda [7, 10] Obakiro et al. Tropical Medicine and Health Page 5 of 21 (2020) 48:68 Table 1 Medicinal plants used in treatment of symptoms of TB in East Africa (Continued) Botanical name Family Local Names Habit Part used Country Author (s) Balanites aegyptiaca (L.) Delile Zygophyllaceae Olngosua (Maasai), Ekorete Shrub Stem bark Tanzania, Kenya; Uganda [10, 12] Bersama abyssinica Fres. Melianthaceae Kipsigriet (Sabaot), Kibuimetiet (Nandi) Tree Leaves Kenya [36] Bidens pilosa L. Asteraceae Sere, Labika (Luganda), Kalala (Lusoga), ononot (Lango) Herb Flowers, Leaves Uganda, Rwanda, [7, 10, 37, Burundi 38] Blighia unijugata Baker Sapindaceae Enkuza nyana (Luganda) Tree Stem bark Uganda [7] Boscia senegalensis (Pers.) Lam. Capparaceae Kursan; Mukheit Shrub Not reported South Sudan [35] Bridelia micrantha (Hochst.) Baill. Euphorbiaceae Katazamitti (Luganda), Umugimbu, Tree Stem bark, Root Uganda, Burundi [7, 38] Brillantaisia owariensis P. Beauv. Acanthaceae Icuga Herb Leaves Uganda [10] Cadaba farinosa Forssk Capparaceae Lumuriai (Samburu), Akado marateng (Luo) Shrub Not reported Kenya [39] Callistemon citrinus (Curtis) Skeels Myrtaceae Mwabalabutonya (Luganda) Shrub Leaves, Stem bark Uganda [7, 9, 10] Canarium schweinfurthii Engl. Burseraceae Muwafu (Luganda), Mubafu (Lusoga, Rutoro) Tree Stem bark, stem, roots Uganda, Kenya [7, 9, 12] Canephora pierre ex A. Froehner Rubiaceae Emwanyi (Luganda) Shrub Stem bark Uganda [7] Capparis erythrocarpos Isert Capparaceae Muzingani omwelu, Kitunku ekitono Shrub Roots Uganda [10] Capparis tomentosa Lam. Capparaceae Muzingani omwelu, Kitunku ekitono Shrub Roots Uganda [10] Carica papaya L. Caricaceae Amapapali, Paapali essajja (Luganda), Mupapali omusaiza (Lusoga), Apapalu (Lango) Shrub Leaves, Stem Uganda [7, 9, 10] Carissa edulis (Forsk.) Vahl Apocynaceae Muyonza, Ekamuriei (Ateso) Shrub Roots Uganda [10] Cassine buchananii Loes. Celastraceae Mbaluka (Luganda) Tree Stem bark, Leaves Uganda [8] Catha edulis Forsk. Celastraceae Chemgangoi (Sabaot) Shrub Stem bark Kenya [36] Celosia trigyna L. Amaranthaceae Kakubaggiri (Luganda) Herb Leaves Uganda [7] Chaetacme aristata Planch. Ulmaceae Embutami (Luganda) Tree Leaves Uganda [7] Cinnamomum zeylanicum Blume Lauraceae Mudalasini (Luganda) Tree Stem bark Uganda [7] Cissampelos pereira L. Menispermaceae Karigi munana Liana Roots Kenya [28] Cissus quinquangularis L. Vitaceae Sukurtuti Herb Roots Kenya [12, 34] Citrus limon (L.) Osbeck Rutaceae Nimawa Tree Fruit Uganda [9] Combretum molle R.Br. ex. G. Don. Combretaceae Ndagi, Loro (Lango) Tree Stem bark Uganda [7, 8, 10] Commiphora species Burseraceae Oltemuai (Sabaot) Shrub Not reported Kenya [40] Commiphora edulis (Klotzsch) Burseraceae Not reported Shrub Stem bark, Leaves Kenya [12, 26] Commiphora ellenbeckii Burseraceae Engl. Not reported Shrub Stem bark, Leaves Kenya [26] Commiphora mildbraedii Engl. Burseraceae Not reported Shrub Stem bark, Root bark Kenya [26] Cordia africana Lam Boraginaceae Not reported Tree Roots Tanzania, Kenya [12] Crassocephalum vitellinum Apiaceae Akayungubira Herb Leaves Burundi [38] Crossopteryx febrifuga Rubiaceae Not reported Tree Roots Tanzania, Kenya [12] Obakiro et al. Tropical Medicine and Health Page 6 of 21 (2020) 48:68 Table 1 Medicinal plants used in treatment of symptoms of TB in East Africa (Continued) Botanical name Family Local Names Habit Part used Country Author (s) Croton dichogamus Pax. Euphorbiaceae Oloiborrbenek (Massai) Shrub Roots Tanzania, Kenya [12] Croton macrostachyus Hochst. ex Del Euphorbiaceae Omutswitswi (Wanga), Mukinduri (Kikuyu) Tree Leaves, Roots Kenya [33] Croton sylvaticus Euphorbiaceae Not reported Tree Roots Tanzania [41] Croton zambesicus Euphorbiaceae Um-Gilagla Tree Fruit South Sudan [42, 43] Cryptolepis sanguinolenta Apocynaceae Kafulu (Luganda) Shrub Roots Kenya, Uganda [12, 44] Cymbopogon citratus D.C. ex Stapf Poaceae Kisubi (Luganda), Akisube (Ateso), Lum cai (Lango) Herb Leaves Uganda [7] (Afzel. ex G.Don) Benth. Cyperus latifolius Poir. Cyperasaceae Ekekeriaut Herb Roots Uganda [10] Cyperus rotundus L. Subsp. rotundus Cyperasaceae Ekekeriaut Herb Roots Uganda [10] Cyphostemma adenocaule Vitaceae Lordo (Samburu) Herb Not reported Kenya [34] Dalbergia melanoxylon Guill. & Perr. Fabaceae Not reported Tree Stem bark Kenya [28] Datura stramonium Solanaceae Not reported Herb Leaves Rwanda [45] Desmodium salicifolium Fabaceae (Poir.) D.C. Enkolimbo (Luganda) Herb Leaves Uganda [7] Desmodium repandum (Vahl) DC. Papilionaceae Ituza Herb Leaves Uganda [10] Dichrostachys cinerea (L.) Wight and Arn Fabaceae Chinjiri (Digo) Tree Roots Kenya [28] Dodonaea angustifolia L. f. Sapindaceae Musambya (Luganda) Shrub Leaves Uganda [10] Dracaena steudneri Engl. Asparagaceae Kajjolyenjovu (Luganda) Tree Stem bark Uganda, Kenya [7, 9, 10, 12] Dychrostachys glomerata (DG) (Forssk.) Fabaceae Not reported Tree Leaves, Roots Uganda, Kenya, Tanzania [10, 12, 29] Embelia schimperi Vatke Myrsinaceae Sachuonet (Ogiek) Tree Stem bark Kenya [46] Entada abbysinica A. Rich. Fabaceae Laginaria (Luo) Mwolola (Luganda) Shrub Roots, Stem bark, Leaves Uganda, Kenya, Tanzania [7, 10, 12, 29] Erythrina abyssinica Lam. ex DC. Fabaceae Ejjirikiti (Luganda), Kiko Omoko (Rutoro), Oluo (Lugbara), Owila kot (Lango), Muyirikiti (Lusoga), Omotembe (Kisii)Muhuti (Kikuyu), Umurinzi Tree Stem bark, leaves Uganda, Kenya, Tanzania, Rwanda, Burundi [7–10, 12, 38, 45, 47] Eucalyptus species Myrtaceae Kalintusi (Luganda) Tree Leaves, Stem bark Uganda, Kenya, [7–10, 12, Tanzania, Rwanda 47, 48] Euclea divinorum Hiern Ebenaceae Emus, Kasalagala/Muda (Lusoga) Shrub Roots Uganda [10] Euphorbia ingens E.Mey. ex Boiss. Euphorbiaceae Not reported Tree Roots Kenya [28] Euphorbia schimperiana Scheele Euphorbiaceae Kazagamira (Luganda) Tree Leaves Uganda [7] Faidherbia albida (Del.) Chevi. Fabaceae Haraz Tree Leaves South Sudan [42] Ficus glumosa Delile Moraceae Muwo (Luganda) Shrub Stem bark Uganda [7] Ficus natalensis Hochst. Moraceae Omutuba (Luganda), Mugaire (Lusoga) Tree Stem bark Uganda [7] Ficus platyphylla Delile Moraceae Mudodwe Shrub Stem bark Uganda [10] Ficus saussureana Moraceae Omuwo (Luganda) Shrub Stem bark Uganda [8] Fleurya aestuans (L.) Gaudich. ex Miq. Urticaceae Munyango (Luganda) Herb Leaves Uganda [7] Obakiro et al. Tropical Medicine and Health Page 7 of 21 (2020) 48:68 Table 1 Medicinal plants used in treatment of symptoms of TB in East Africa (Continued) Botanical name Family Local Names Habit Part used Country Author (s) Garcinia buchananii Baker Clusiaceae Musaali (Luganda) Tree Stem bark, Root bark Uganda, Kenya, Tanzania [7, 10, 12] Gnaphalium purpureum L. Asteraceae Omuya (Luganda) Herb Leaves Uganda [7] Gnidia buchananii Gilg Thymelaeaceae Not reported Herb Roots Kenya [49] Gomphocarpus physocarpus E. Mey. Apocynaceae Gashaho Herb Leaves Uganda [10] Gutenbergia cordifolia Benth. ex Oliv. Asteraceae Ekoutapem Herb Roots, Leaves Uganda [10] Harrisonia abyssinica Oliv. Simaroubaceae Mutagataga (Meru), Osiro (Luo), Orongoriwe (Kuria), Lushaike Shrub Stem bark Uganda, Kenya [10, 50, 51] Harungana madagascariensis Lam.ex Pior Hypericaceae Mukabiiransiko (Luganda) Tree Stem bark, Leaves Uganda [8] Helichrysum odoratissimum (L.) Asteraceae Lweza (luganda) Herb Leaves Uganda [10] Heterotis canescens Melastomataceae Umusomaw’a-bungere, Herb Leaves Burundi [38] Hibiscus fuscus Garcke Malvaceae Lusaala (Luganda) Herb Leaves Uganda [7] Hoslundia opposita Vahl Lamiaceae Cheroronit, Cherungut (Nandi), Nfodo (Lusoga) Shrub Leaves Uganda, Kenya [10, 31] Hypericum revolutum Vahl Clusiaceae Mushungwa Tree Leaves Uganda [10] Hypoestes verticillaris (L.f.) Sol. Acanthaceae Narubat (Ogiek) Herb Roots Kenya [46] Iboza multiflora (Benth.) E. A. Bruce Lamiaceae Iseja Shrub Leaves Uganda [10] Iboza riparia (Hochst.) N. E. Br. Lamiaceae Muravumba Shrub Leaves Uganda [10] Indigofera emarginella Steud. ex A. Rich. Fabaceae Olutunga nsonzi (Luganda) Shrub Leaves, Stem bark Uganda [7] Indigofera lupatana Baker F Fabaceae Not reported Shrub Roots Kenya [28] Kalanchoe glaucescens Planch. ex Benth Crassulaceae Ekiyondo ekyeru (Luganda) Herb Leaves Uganda [7, 9] Kalanchoe integra Crassulaceae Not reported Shrub Leaves Rwanda [48] Khaya senegalensis Meliaceae Not reported Tree Leaves, Stem bark South Sudan [52] Lagenaria sphaerica (Sond.) Naudin Cucurbitaceae Mutanga Herb Leaves Uganda [10] Lantana camara L. Verbenaceae Kayukiyuki (Luganda), Owinybilo (Lango), Kanpanga (Ateso) Shrub Leaves Uganda [7, 10, 53] Lantana trifolia Verbenaceae Not reported Shrub Leaves Rwanda [48] Leonotis nepetifolia (L.) R. Br. Lamiaceae Susuni Shrub Leaves Uganda [10] Leucas calostachys Oliv. Lamiaceae Kakuba musulo (Luganda) Shrub Leaves, Whole Uganda plant [8] Lippia grandifolia Hochst. ex A. Rich Verbenaceae Olugumaguma (Luganda) Herb Leaves Uganda [7] Lonchocarpus eriocalyx Harms Fabaceae Not reported Tree Stem bark Kenya [11, 28] Maesa lanceolata Forssk. Myrsinaceae Muhanga Tree Roots Uganda [10] Mangifera indica L. Anacardiaceae Muyembe (Luganda), Aeme (Lango) Tree Stem bark Uganda, Kenya [7, 9, 10, 12, 47] Maytenus senegalensis Celastraceae Naligwalimu (Luganda), Muwaiswa, Eterka, Itereka Shrub Root bark, Uganda [7, 10] Obakiro et al. Tropical Medicine and Health Page 8 of 21 (2020) 48:68 Table 1 Medicinal plants used in treatment of symptoms of TB in East Africa (Continued) Botanical name Family (Lam.) Local Names Habit (Lango) Part used Country Author (s) Leaves Microglossa pyrifolia (Lam.) Asteraceae Kabilili akatono (Luganda) Shrub Roots Uganda [10] Microgramma lycopodiodes (L.) Copel Polypodiaceae Kukumba (Luganda) Herb Roots, Leaves Uganda [8] Milicia excelsa (Welw.) C.C. Berg Moraceae Muvule (Luganda) Tree Leaves Uganda [7] Momordica foetida Schumach. Cucurbitaceae Bombo (Luganda), Luiwula/Mwishwa Herb Leaves Uganda, Rwanda [7, 10, 45] Momordica rostrata A. Zimm. Cucurbitaceae Chepkologolio (Ogiek) Herb Roots Kenya [46] Morella kandtiana (Engl.) Verdc. & Polhill Myricaceae Mukikimbo (Luganda) Herb Roots, Leaves, Uganda Whole plant [8] Morinda lucida Benth. Rubiaceae Kabaja nsayi (Luganda) Tree Stem bark Uganda [7] Moringa oleifera Lam. Moringaceae Moringa (Luganda) Tree Fruit, Stem Uganda [7, 10] Mucuna pruriens (L.) DC. Papilionaceae Lugenyu (Luganda) Vine Leaves Uganda [10] Myrica kandtiana Engl. Myricaceae Enkikimbo(Luganda) Tree Fruit, Leaves, Stem bark, Root bark Uganda [7] Myrsine africana L. Myrsinaceae Seketeti (Samburu) Shrub Not reported Kenya [34] Nauclea latifolia Sm Rubiaceae Karmadoda Tree Fruit South Sudan [54] Ocimum basilicum Lamiaceae Umusurasura Herb Leaves Burundi [38] Ocimum suave Willd. Lamiaceae Muhumuzanganda (Luganda) Herb Leaves Uganda [10] Olea capensis L. Oleaceae Pekeriondet (Sabaot) Tree Stem bark Kenya [36] Olinia rochetiana Penaeaceae Kaptolongit (Sabaot) Tree Roots Kenya [36] Ormocarpum trichocarpum (Taub.) Harms Papilionaceae Eseperuae Tree Roots Uganda [10] Pappea capensis (Spreng) Eckl. & Zeyh. Sapindaceae Muba (Kikuyu), Enkorrirri, Oltimigomi (Maasai) Shrub Stem bark, Root bark Kenya [55, 56] Parinari curatellifolia Planch. ex Benth. Chrysobalanaceae Umunazi Tree Stem bark, roots Burundi [38] Pavetta crassipes K. Schum. Rubiaceae Not reported Shrub Roots Tanzania, Kenya [12] Pentas longiflora Oliv. Rubiaceae lsagara Herb Roots Rwanda [37] Persea americana Mill. Lauraceae Ovacado (Luganda) Tree Stem bark Uganda [7, 9] Phaseolus lunatus L. Fabaceae Kayindiyindi (Luganda) Herb Leaves Uganda [7] Phaseolus vulgaris L. Fabaceae Bijanjaro (Luganda) Herb Husks Uganda [7] Phyllanthus reticulatus Poir. Phyllanthaceae Mutulika (Luganda) Shrub Leaves Uganda [7] Piliostigma thonningii Fabaceae Chebutiandet (Sabaot) Tree Leaves Kenya [36] Piptadenistrum africana Fabaceae Mpewere (Luganda) Tree Stem bark Uganda [7, 9, 10] Plectranthus barbatus Andrews Lamiaceae Ekibankulata (Luganda), Ebiriri omutano (Ateso) Shrub Leaves Uganda [7, 10] Plectranthus hadiensis Lamiaceae Kibwankulanta (Luganda) Shrub Whole plant, Leaves Uganda [8] Plumbago dawei Plumbaginaceae Lkiarianthus (Samburu) Herb Stem bark Kenya [29] Plumbago zeylanica L. Plumbaginaceae Musajjabanda (Luganda), Mukya (Kamba) Herb Leaves Uganda, Kenya [7, 34, 57] Podocarpus usambarensis Pilg. Podocarpaceae Kamusenene (Luganda) Tree Leaves Uganda [7] Prunus africana (Hook.f.) Kalkman Rosaceae Ntaseesa, Ngwabuzito (Luganda, Rutoro),Sirumandu (Lugisu) Tree Stem bark Uganda [7] Obakiro et al. Tropical Medicine and Health Page 9 of 21 (2020) 48:68 Table 1 Medicinal plants used in treatment of symptoms of TB in East Africa (Continued) Botanical name Family Local Names Habit Part used Country Author (s) Pseudospondia microcarpa (A. Rich.) Engl. Anacardiaceae Muziru (Luganda) Tree Stem bark Uganda [7] Psidium guajava L. Myrtaceae Mpera (Chagga) Tree Fruit, Leaves, Stem bark, Root bark Uganda, Kenya, Tanzania [7, 12] Pycnostachys ericirosenii Lamiaceae R.E.Fr. Musindikwa (Luganda) Shrub Leaves Uganda [10] Rhamnus prinoides L’Herit. Rhamnaceae Munanira (Luganda) Shrub Leaves Uganda [10] Rhoicissus tridentata (L.f.) Wild. & R.B.D. Drumm. Vitaceae Mumara (Luganda) Shrub Leaves Uganda [10] Rhus natalensis Bernh. ex Krauss Anacardiaceae Lmisigiyoi, Muthigiu (Kikuyu) Tree Roots, Leaves Kenya [51] Rhus vulgaris Meikle Anacardiaceae Kakwansokwanso (Luganda) Herb Stem bark, Leaves Uganda [7] Ribes uva-crispa L. Grossulariaceae Entuntunu (Luganda) Shrub Leaves Uganda [7] Rosmarinus officinalis L. Lamiaceae Not reported Herb Leaves South Sudan [52] Rubia cordifolia L. Rubiaceae Kasalabakesi (Luganda) Urumurwa (Kuria) Herb Leaves, Whole Uganda, Kenya, plant Tanzania [7, 9, 10, 12, 16] Rumex abyssinicus Jacq. Polygonaceae Not reported Herb Leaves Rwanda [48] Sapium ellipticum (Hochst.) Pax Euphorbiaceae Omusasa (Luganda) Shrub Stem bark Uganda [7] Securidaca longipedunculata Fresen. Polygalaceae Mukondwa, Awee ilila (Lango), Mukondwa (Lusoga), Eliloi (Ateso) Tree Roots Uganda [8, 10] Senna siamea (Lam.) Irwin & Barneby Fabaceae Gasiya seed Tree Stem bark Uganda [10] Sesamum calycinum Pedaliaceae Lutungotungo (Luganda) Herb Leaves, Whole Uganda plant [8] Solanum aculeastrum Dunal Solanaceae Mutura (Kikuyu), Ekitengo (Luganda) Shrub Fruit, Roots, Leaves Uganda, Kenya [7, 8, 12] Solanum incanum L. Solanaceae Entengotengo Ennene (Luganda), Ocokocok (Lango), Ntonka (Lusoga), Mutongu (Kamba),Entulelei (Maasai) Shrub Fruit Uganda, Kenya [7, 12] Solanum mauense Bitter Solanaceae Ng’onyoyiek (Ogiek) Shrub Seeds Kenya [46] Spathodea campanulata P. Beauv. Bignoniaceae Kifabakazi (Luganda) Tree Stem bark Uganda [7] Syzygium cumini (L.) Skeels Myrtaceae Jambula (Luganda) Tree Stem bark Uganda [7, 9] Tamarindus indica L. Fabaceae Mukoge (Luganda), Cwao (Lango) Tree Leaves Uganda [10] Teclea nobilis Del. Rutaceae Luzo Shrub Leaves Uganda [10] Tetradenia riparia (Hochst.) Codd Lamiaceae Ekyewamala (Luganda) Herb Leaves Uganda, Rwanda [7, 37] Terminalia laxiflora Engl. & Diels Combretaceae Darout Tree Stem bark South Sudan [30] Tithonia diversifolia (Hemsl.) A. Gray Asteraceae Ekimyula, Okelokelo (Lango) Shrub Stem bark Uganda [7] Toddalia asiatica (L.) Lam Rutaceae Simborichet (Sabaot), Mururue (Kikuyu), Oleparmunyo (Maasai), Kawule (Luganda) Shrub Roots, Leaves Uganda, Kenya [7, 8, 10, 36] Tragia brevipes Pax Euphorbiaceae Nakepian Climber Roots Uganda [10] Tragia subsessilis Pax Euphorbiaceae Totoananyia Herb Roots Uganda [10] Trichilia dregeana Sond. Meliaceae Sekoba (Luganda) Tree Stem bark, Uganda [7] Obakiro et al. Tropical Medicine and Health Page 10 of 21 (2020) 48:68 Table 1 Medicinal plants used in treatment of symptoms of TB in East Africa (Continued) Botanical name Family Local Names Habit Part used Country Author (s) Triumfetta flavescens Hochst. ex A. Rich. Malvaceae Luwugula (Luganda) Shrub Stem Uganda [7] Vachellia drepanolobium (Harms ex Sjostedt) P.J.H. Huter Fabaceae Oluai (Maasai) Tree Stem bark, Root bark Kenya [55] Vernonia cinerea (L.) Less. Asteraceae Kayayana, Lukohe (Luganda), Yat Kwong (Lango) Herb Leaves Uganda [7] Vernonia amygdalina Del. Asteraceae Mululuza (Luganda) Lubilili Shrub Leaves Uganda [7, 10] Warburgia ugandensis Sprague Canellaceae Abaki, Sokoni (Samburu), Muthiga (Kikuyu) Tree Stem bark Uganda, Kenya, Tanzania [7–10, 12, 16, 57– 59] Zanthoxylum chalybeum Engl. Rutaceae Ntale ya ddungu (Luganda), Eusuk (Ateso), Agodaman (Lango), Oloisuki (Maasai), Rukuts (Karimojong), Outiku (Lugbara) Tree Stem bark Uganda, Kenya, Tanzania [5, 8–10, 12] Zanthoxylum gillettii (De Wild.) P.G. Waterman Rutaceae Sagawatiet, Shihumba/Shikuma Tree Stem bark Kenya [31] [5] Zanthoxylum leprieurii Rutaceae Not reported Tree Stem bark Uganda Zehneria scabra Cucurbitaceae Umushishiro, Herb Leaves Burundi [38] Zingiber officinale Zingiberaceae Tangawizi (Luo), Ntangawuzi (Luganda) Herb Stem Uganda, Kenya [7, 9, 10, 12] Languages: Ateso, Lango, Luganda, Lugbara, Lugisu, Lusoga, Karimojong, and Rutoro (Uganda); Digo, Kamba, Kikuyu, Kisii, Kuria, Luo, Maasai, Meru, Nandi, Ogiek ,Sabaot, Samburu, and Wanga (Kenya); and Chagga (Tanzania). Local names with language(s) not indicated were not specified by the authors pathways that produce majorly flavonoids, terpenoids, and alkaloids as secondary metabolites [73–75]. It is these phytochemicals that are responsible for the antimycobacterial activity against different mycobacterial strains [67, 70, 76, 77]. Other families reported in East Africa to house medicinal plants for management of TB and have also been reported in other countries include Acanthaceae, Apocynaceae, Cariaceae, Combretaceae, Malvaceae, Moraceae, Myrtaceae, Rhamnaceae, Rubiaceae, Solanaceae, and Zingiberaceae [64, 72, 78–81]. Geographically, none of the documented plant species was reported to be used in the management of TB across all the East African countries. However, two plant species (Erythrina abyssinica and Eucalyptus species) are used by at least 4 countries. A total of 30 plant species were reported to be used by at least two countries. Uganda had the highest number of species mentioned followed by Kenya and then Tanzania (Table 1). The differences in species utilization could be attributed to the differences in soil chemistry, rainfall, topography, and climate that results into differences in phytochemical composition of the same species growing in different geographical areas [82]. Additionally, it could also be due to differences in knowledge and experiences as result of different social and cultural backgrounds that exists across the countries. Uganda had many ethnobotanical surveys conducted to document medicinal plants used in the management of tuberculosis as compared to other countries. Most of these medicinal plants were growing as trees (40.0%), herbs (29.7%), shrubs (27.7%), and rarely as climbers, vines, or lianas (Fig. 3). Analysis of ethnomedicinal recipes revealed that mainly leaves (38.6%), stem bark (28.4%), and roots (18.6%) were used for preparing herbal remedies. Root bark, whole plants, fruits, flowers, seeds, and husks were rarely used (Fig. 4). Harvesting of leaves and stem bark allows sustainable utilization of the plants hence promoting their conservation as opposed to use of roots and whole plants. Additionally, leaves are the primary sites for secondary metabolic pathways in plants while stem barks act as major concentration areas (deposition sites) for the synthesized metabolites [9, 57]. Most articles reviewed reported that traditional herbal medicine practitioners usually combined different plant species while preparing herbal medicines. However, they did not report how the herbal medicine from individual plant species can be prepared. Decoction was by far the commonest method of herbal medicine preparation cited. Others included cold infusions, drying and pounding into a powder, burning into ash, chewing, and steaming. Use of more than one plant in combination is more effective than single plant perhaps due to the synergistic interactions that occur among the different phytochemicals that result into increased bioactivity (efficacy). But also, the benefit of phytochemicals from Obakiro et al. Tropical Medicine and Health Page 11 of 21 (2020) 48:68 Fig. 1 Major botanical families from which TB remedies are obtained in East Africa one species counteracting the toxicity of another species could be another explanation. The major route of administration was oral (via the mouth) although sometimes inhalation and topical application were also reported depending on the preparation method used and the toxicity of the plant(s). Cups, bottles, and tablespoons were the most commonly used for determining the posology of herbal remedies [7, 10, 12]. Efficacy and safety studies Some ethnobotanical studies reported that herbal medicine preparations were effective in the treatment of TB, while some were used in the management of multidrugresistant tuberculosis [7, 12, 47]. This could be due to the synergistic interaction between the various phytochemicals present in the herbal preparations [27, 83]. However, as much as these herbal medicines might have genuine bioactivity, sometimes they are used concurrently with conventional therapies as supplements and at times adulterated. Therefore, it is important to scientifically validate the claimed efficacy and safety of both the herbal preparations and the individual medicinal plants. Out of the 195 species documented, only 36 plant species (18.5%) have been studied for their antimycobacterial activity. A WHO report [14] indicated that only approximately 10% of the world’s flora have been studied as regards their medicinal potential. This has greatly hindered the discovery of potential lead compounds that could be developed into new antitubercular drugs. Obakiro et al. Tropical Medicine and Health (2020) 48:68 Fig. 2 The most cited plant species used for treatment of TB and its symptoms in East Africa Fig. 3 Growth habit of the plants used for preparation of antitubercular remedies in East Africa Page 12 of 21 Obakiro et al. Tropical Medicine and Health Page 13 of 21 (2020) 48:68 Fig. 4 Frequency of plant parts used for preparation of antitubercular remedies in East Africa Out of the 36 screened medicinal plants, 31 species (86.1%) were reported to be bioactive with some species exhibiting quite considerable antimycobacterial activity although the current standard drugs had superior bioactivity (Table 2). This is comparable to India where 70% of 365 plants which were studied showed antimycobacterial activity [87]. Among the promising plant species (with minimum inhibitory concentration less than 0.5 mg/ml) were Erythrina abyssinica, Entada abyssinica, Bidens pilosa, Callistemon citrinus, Khaya senegalensis, Lantana camara, Piptadenistrum africana, Rosmarinus officinalis, Tetradenia riparia, and Zanthoxylum leprieurii. Isolated pure compounds from three of the promising plant species had much higher activity against Mtb than the crude extracts and fractions. Indeed, some of the compounds from Zanthoxylum leprieurii had minimum inhibitory concentrations lower than those of standard antitubercular drugs (Table 3). Crude extracts and fractions usually have less pharmacological activity than standard drugs because of the interference from other inactive substances in the matrix that reduce the overall concentration of the active molecules in the tested dose. This explains why isolation of pure compounds is a critical step in natural product drug discovery process. The five documented medicinal plants that were found to be inactive are Acacia ataxacantha, Dalbergia melanoxylon, Indigofera lupatana, Lonchocarpus eriocalyx, and Solanum incanum. This could probably be attributed to the absence of inherent bioactive phytochemicals against Mtb in the plant species. This could be brought about by absence or impaired biosynthetic metabolic pathways due to unfavorable growth conditions in the habitat from where the plants grow. This implies that herbal remedies for TB containing each of these plants singly may not be effective. Therefore, other benefits provided by these species in the concoctions of TB such as detoxification of other toxic phytochemicals, preservation of the herbal medicine, or potentiation of the pharmacological activity of other phytochemicals could be investigated. All toxicity studies reviewed evaluated only the acute toxicity profiles of the medicinal plants either in vitro or in vivo but not both. Of the bioactive extracts screened, less than half of them were tested for their acute toxicity. Selectivity index (SI) is used as the best estimate of the relative toxicity of a compound to normal mammalian cells as compared to the pathogen and hence its suitability for being a drug candidate. According to the SI criterion, compounds with higher SI are regarded to have better toxicity profiles than those with lower SI [88]. From the retrieved data, only two plant species (Khaya senegalensis and Rosmarinus officinalis) had acceptable selectivity indices to warrant drug discovery from them. In this study, the SI of only five plant species could be Obakiro et al. Tropical Medicine and Health Page 14 of 21 (2020) 48:68 Table 2 Efficacy, toxicity, and phytochemical studies on medicinal plants used for treatment of TB in East Africa Plant Extraction method MIC (μg/ml) on (solvent) H37Rv strain MIC (μg/ml) on TMC-331 strain Toxicity of crude extracts (μg/ml) Class of compounds Author(s) Acacia ataxacantha Maceration (methanol) Not tested IC50 = 90.39 Phenols, terpenoids [28] Acacia horrida Soxhlet (methanol) < 1000 (Iso < 500) Not tested Not tested Alkaloids, cardiac glycosides, tannins, saponins, terpenoids [29] Acacia senegal Soxhlet (methanol) < 1000 (Iso < 500) Not tested Not tested Cardiac glycosides, tannins, saponins, terpenoids, flavonoids [29] Acokanthera friesiorum Soxhlet (methanol) < 1000 (Iso < 500) Not tested Not tested Cardiac glycosides, Tannins, flavonoids [29] Albizia anthelmitica Soxhlet (methanol) < 1000 (Iso < 500) Not tested Not tested Alkaloids, saponins, tannins, flavonoids [29] Not active Aspilia pluriseta Maceration (methanol) Active at 1 g/ml (MIC not determined) Not tested IC50 = 24.51 Phenol, terpenoids, flavonoids [28] Bidens pilosa Maceration (ethanol) 100 Not tested Not tested Not tested [37] Callistemon citrinus Maceration (methanol, chloroform) 325 (methanol), 48 (chloroform) 78 (methanol), 158 (Iso = 4.0; R = 2.0) (chloroform), Iso = 4.0 Not tested Flavonoids, alkaloids, triterpenoids, saponins [15] Cissampelos pareira Maceration (methanol) Active at 1 g/ml (MIC not determined) Not tested IC50 = 179 Anthraquinones, phenols, [28] terpenoids, flavonoids Commiphora edulis Maceration (ethyl acetate, DCM, water) 6250 (Ethyl acetate), 780 (methanol), Not active (water) Not tested IC50 = 393 (DCM), Flavonoids, terpenoids 1734 (ethyl acetate) [26] Commiphora ellenbeckii Maceration (ethyl 12500 (Ethyl acetate), 3125 acetate, methanol, (methanol), 780 (water), 15 (rif) water) Not tested IC50 = 608 (methanol), 1509 (water) Alkaloids, saponins, tannins, phenols, flavonoids, terpenoids [26] Commiphora mildbraedii Maceration (ethyl 6250–9250 (Ethyl acetate), 390– Not tested acetate, methanol, 780 (methanol), not active water) (water), 15 (Rif) IC50 = 339 (ethyl acetate), 452 (methanol) Alkaloids, saponins, tannins, phenols, flavonoids, terpenoids [26] Cordia sinensis Soxhlet (methanol) < 500 (Iso < 500) Not tested Not tested Saponins, terpenoids, flavonoids, tannins [29] Cryptolepsis sanguinolenta Methanol chloroform 1170 (methanol) (Iso = 0.25; R = 0.25) 1580 (methanol) (Iso = 0.25) LD50 = 758 mg/ kg Alkaloids, tannins, flavonoids [84] Dalbergia melanoxylon Maceration (methanol) Not active Not tested IC50 = 120.04 Phenols, terpenoids [28] Dichrostachys cinerea Maceration (methanol) Active at 1 g/ml, (MIC not determined) Not tested IC50 = 201.22 Phenols, terpenoids [28] Entadda abyssinica Maceration (methanol) 500 (Iso = 0.25) Not tested Not tested Flavonoid, alkaloids, saponins, tannins [12, 29] Erythrina abyssinica Maceration (methanol) 390 (Rif = 0.25; Iso = 0.25) 2350 (Iso = 9.38) LD50 = 776.2 mg/ Flavonoids, alkaloids, tannins kg [44] Euphorbia ingens Maceration (methanol) Active at 1 g/ml (MIC not determined) Not tested IC50 = 105.55 Phenols, terpenoids [28] Euphorbia scarlatica Soxhlet (methanol) < 500 (Iso < 500) Not tested Not tested Alkaloids, cardiac glycosides, terpenoids, flavonoids [29] Gnidia buchananii Maceration (methanol) Active at 1 g/ml (MIC not determined) Not tested IC50 = 76.24 Phenols, terpenoids, [28] Indigofera lupatana Maceration (methanol) Not active Not tested IC50 = 60.37 Phenols, terpenoids [28] Khaya senegalensis Maceration (ethyl acetate, chloroform) 6.25 Not tested IC50 = 1000 Not tested [52] Obakiro et al. Tropical Medicine and Health Page 15 of 21 (2020) 48:68 Table 2 Efficacy, toxicity, and phytochemical studies on medicinal plants used for treatment of TB in East Africa (Continued) Plant Extraction method MIC (μg/ml) on (solvent) H37Rv strain MIC (μg/ml) on TMC-331 strain Toxicity of crude extracts (μg/ml) Class of compounds Author(s) Lantana camara Maceration (methanol, chloroform) 20 (Rif = 1) 15 (Iso = 0.25) LD50 > 500 mg/ kg Not reported [53] Lonchocarpus eriocalyx Maceration (methanol) Not active Not tested IC50 = 201.87 Terpenoids, phenols, flavonoids [28] Loranthus acaciae Soxhlet (methanol) < 1000 (Iso < 500) Not tested Not tested Alkaloids, cardiac glycosides, saponins, flavonoids [29] Mangifera indica Methanol 3130 (methanol) (Iso = 0.25; R = 0.25) 590 (methanol) (Iso = 0.25) Not tested Phenols, terpenoids [16] Pentos longiflora Maceration (ethanol) 1000 Not tested Not tested Not tested [37] Piptadenistrum africana Maceration (chloroform) 395 (chloroform) 395 (chloroform) Not tested Flavonoids, tannins [15] Plumbago dawei Soxhlet (methanol) < 1000 (Iso < 500) Not tested Not tested Cardiac glycosides, tannins, terpenoids, flavonoids [29] Rosmarinus officinalis L. Maceration (chloroform) Not tested IC50 = 100 Not tested [52] Salvadora persica Soxhlet (methanol) < 500 (Iso < 500) Not tested Not tested Alkaloids, cardiac glycosides, terpenoids, flavonoids [29] Solanum incanum Methanol chloroform Not active Not active Not tested Not reported [16] Tetradenia riparia Maceration (ethanol) 500 Not tested Not tested Not tested [37] Warburgia ugandensis Methanol chloroform 4690 (methanol), 2350 (chloroform) (Iso = 0.25; R = 0.25) 2350 (methanol), 590 (chloroform) (Iso = 0.25) Not tested Flavonoids, tannins, terpenoids [85, 86] Zanthoxylum leprieurii Methanol 47.5 (Iso = 4.0; R = 2.0) 75.3 (Iso = 4.0) Not tested Alkaloids [5] 6.25 IC50 median cytotoxic concentration, LD50 median lethal dose, Iso isoniazid, Rif rifampicin, H37Rv pan sensitive Mtb strain, TMC331 rifampicin-resistant Mtb strain, MIC minimum inhibitory concentration. Extracts in [26] were tested against Mycobacteria smegmatis calculated (Table 4) because they were the only plant species with both the inhibitory concentration on Mtb and cytotoxic concentration on normal mammalian cell lines (IC50) reported. Hence, there is need to emphasize dual testing of both toxicity and efficacy of natural products for drug development purposes. Two other systems of acute toxicity classification: The National Cancer Institute (NCI) and Organization for Economic cooperation and development (OECD) guidelines 423 were used to assess the toxicity profiles of the different extracts [89, 90]. There was no single plant species among those tested for acute toxicity that was reported to be highly toxic (with IC50 less than 20 μg/ml). All the plant species with promising bioactivity that were tested for toxicity had acceptable acute toxicity profiles. These included Rosmarinus officinalis, Lantana camara, Khaya senegalensis, and Erythrina abyssinica (Table 2). Aspilia pluriseta, Cissampelos pareira, Euphorbia ingens, and Gnidia buchananii had moderate toxicity with IC50 between 20 and 200 μg/ml. According to OECD 2001 Table 3 Isolation and characterization studies on medicinal plants used for management of TB in East Africa Plant Pure compounds with antitubercular activity Zanthoxylum leprieurii 2-hydroxy-1, 3-dimethoxy-10-methyl-9-acridone (1), Acridone alkaloids 1.5 (1), 0.2 (2), 0.4 (3); tested against H37Rv 1-hydroxy-3-methoxy-10-methyl-9-acridone (2), 3-hydroxy-1, 5, 6-trimethoxy-9-acridone (3) Chemical class MIC of pure compounds (μg/ml) Author(s) [5] Warburgia ugandensis Sprague Muzigadial (4), muzigadiolide (5), linoleic acid (6) Sesquiterpenes 64 (4), 128 (5), 16 (6); tested against M. smegmatis [58, 85] Tetradenia riparia Diterpenediol 25–100 [37] 15- sandaracopimaradiene-7α, 18-dio1 (7) MIC minimum inhibitory concentration. No toxicity studies of the pure compounds were conducted. Obakiro et al. Tropical Medicine and Health Page 16 of 21 (2020) 48:68 Table 4 Selectivity indices of some antitubercular plant species reported in East Africa Plant Solvent MIC on Mtb strain (μg/ ml) Commiphora edulis Dichloromethane 1560 IC50 (μg/ ml) SI Comment 393 0.25 More toxic to human cells than the Mtb; not useful Ethyl acetate 3125 1734 0.55 More toxic to human cells than the Mtb; not useful Water 780 1509 1.93 More toxic to Mtb than human cells but the SI is low. May be optimized for lead candidate identification Methanol 3125 608 0.19 More toxic to human cells than the Mtb; not useful Methanol 390 452 1.16 More toxic to Mtb than human cells but the SI is close to 1. No practical application Ethyl acetate 6250 339 0.054 More toxic to human cells than the Mtb; not very useful Khaya senegalensis Chloroform 6.25 1000 160 More toxic to Mtb than human cells with high SI. Promising for development of lead candidate Rosmarinus officinalis L. Chloroform 6.25 100 16 More toxic to Mtb than human cells with high SI. Promising for development of lead candidate Commiphora ellenbeckii Commiphora mildbraedii IC50 cytotoxic concentration normal cells, SI selectivity index guidelines, Lantana camara, Erythrina abyssinica, and Cryptolepis sanguinolenta had slight toxicity as their median lethal doses (LD50) were above 500 mg/kg. These results justify the general public belief that traditional medicines are relatively safer as compared to the current conventional therapies. However, toxicity testing should be done on all potential medicinal plants and their phytochemicals before concluding that they are safe for human treatment [91–94]. This is because toxicity of herbal medicines may be due to presence of inherent poisonous chemicals in the plant species, misidentification of the plant species, adulteration or contamination during harvesting, preparation, and storage [95, 96]. Acute toxicity tests determine a single high dose that kills 50% of the cells or animals in a population. They may not be evident enough to depict the real toxicity situation for herbal remedies taken for a longer time in chronic conditions like TB [18, 97]. Therefore, this may necessitate sub-chronic and chronic toxicity tests to be carried out on a medicinal plant species with a potential lead compound [95]. Phytochemistry of the reported plants Phytochemical investigation reveals the chemical nature of the pure compounds that are responsible for the pharmacological activity as well as the toxicity of medicinal plants [19, 64, 98–101]. Chromatographic and spectroscopic techniques are used to identify and elucidate the chemical structures of compounds [102–107]. In this study, maceration was the commonly used method of extraction as compared to Soxhlet. Majority of the hexane extracts were reported to be inactive against mycobacterial strains while almost all methanolic extracts were active. Methanol being a polar solvent extracts polar phytochemical while hexane (a non-polar solvent) extracts non-polar compounds. It is reasonable to assert that the antimycobacterial activity of the extracts is largely due to polar phytochemicals. There were variations in bioactivity of different parts of the same plant with no specific patterns. This could be due to differences in their rate of accumulating the bioactive substances. The phytochemicals that were frequently screened for have been alkaloids, saponins, cardiac glycosides, flavonoids, terpenoids, and phenols. All these secondary metabolites were reported to be present in different bioactive extracts. The most commonly reported phytochemicals were flavonoids, terpenoids, and alkaloids [15, 17, 26, 29, 70, 106, 108]. Flavonoids and alkaloids were reported to be absent in three out of the five inactive plants (Table 2). Out of the 31 bioactive plant species, only three (Tetradenia riparia, Warburgia ugandensis, and Zanthoxylum leprieurii) have been further characterized to identify the pure compounds responsible for their antimycobacterial activity [5, 37, 58, 85] (Table 3). This is attributed to the complexity and the rigorous nature of the process that require extraction, screening, isolation, and characterization [100, 109, 110]. Low extraction yield, compound instability, high costs, low technology especially in developing countries, limited access to advanced chromatographic, and spectroscopic equipment and inadequate funding have made it difficult to undertake herbal medicine research [21, 111, 112]. This is further complicated by the microbiological nature of the Mtb that require bioassays to be conducted in biosafety level 3 laboratories that are not readily available in East Africa [60, 113]. More robust and effective techniques are required to fasten the drug discovery process against TB [3, 77, 92, 114]. A total of seven pure compounds have been isolated and characterized with bioactivity against Mtb (Fig. 5). These are 2-hydroxy-1,3-dimethoxy-10-methyl-9-acridone (1), 1-hydroxy-3- methoxy-10-methyl-9-acridone (2), 3-hydroxy-1, 5, 6-trimethoxy-9-acridone (3), Obakiro et al. Tropical Medicine and Health (2020) 48:68 Page 17 of 21 Fig. 5 Structure of antitubercular molecules isolated in claimed medicinal plants in East Africa. The numbers 1–7 correspond to the molecules mentioned in Table 3 muzigadial (4), muzigadiolide (5), linoleic acid (6), and 15-sandaracopimaradiene-7α, 18-dio1 (7). Compounds 1, 2, and 3 are acridone alkaloids; 4, 5, and 6 are sesquiterpenes, while 7 is a diterpenediol [5, 37, 85]. In Asia and America, several studies have reported pure compounds isolated from medicinal plants to have promising antimycobacterial activity [78, 115–117]. For example, Bisbenzylisoquinoline alkaloids from Tiliacora triandra (tiliacorinine, tiliacorine and 2′-nortiliacorinine) were found to have comparable antimycobacterial activity (MIC = 0.7–6.2 μg/ml) to the standard first line drugs against sensitive and resistant Mtb strains [108]. Rukachaisirikul et al. [118] reported that 5- hydroxysophoranone (an isoflavone from Erythrina stricta) had promising antimycobacterial activity (MIC = 12.5 μg/ml) against Mtb H37Ra. Vasicine acetate and 2-acetyl benzylamine isolated from hexane extract of Adhatoda vasica Ness. (Acanthaceae) inhibited one sensitive and multidrug-resistant strain at 50 and 200 μg/ml respectively [119]. Since flavonoids and alkaloids were reported to be absent in three out of the five inactive plants [28] and majority of the isolated bioactive pure compounds belong to the class of alkaloids, terpenoids, and flavonoids [5, 85, 118], it implies that these classes of phytochemicals are the ones most likely to be responsible for the observed antimycobacterial activity. Conclusion East Africa has a rich diversity of medicinal plants that have been reported to be effective in the management of symptoms of TB. Most of the plants are from the family Fabaceae, Lamiaceae, and Asteraceae. A large proportion of the documented plants have not been scientifically validated for their efficacy and safety. Although the standard drugs had superior activity, majority of the validated plants were found to possess acceptable acute toxicity profile on animal cells and considerable bioactivity with isolated pure compounds showing promising efficacy against Mtb. We recommend more scientific validation studies to be conducted on the remaining plants in order to standardize herbal medicine use and also promote drug discovery and development against TB. More Obakiro et al. Tropical Medicine and Health Page 18 of 21 (2020) 48:68 isolation and characterization studies will enrich the chemical diversity of both the natural product and synthetic chemical libraries from which possible lead candidates could be developed. Currently, we are working on isolation and characterization of bioactive compounds from selected medicinal plants from family Fabaceae identified from this study. These include Erythrina abyssinica, Albizia coriaria, and Entada abyssinica. Supplementary information Supplementary information accompanies this paper at https://doi.org/10. 1186/s41182-020-00256-1. Additional file 1: Figure S1. PRISMA flow diagram used for the review. Abbreviations IC50: Median cytotoxic concentration; LD50: Median lethal dose; Iso: Isoniazid; MIC: Minimum inhibitory concentration; Rif: Rifampicin; H37Rv: Pan sensitive Mtb strain; TMC331: Rifampicin-resistant Mtb strain; SI: Selectivity Index; TB: Tuberculosis; WHO: World Health Organization Acknowledgements The authors are grateful to the World Bank and the Inter-University Council of East Africa (IUCEA) for the scholarship awarded to SBO, MPO, and TO through the Africa Centre of Excellence II in Phytochemicals, Textiles and Renewable Energy (ACE II PTRE) at Moi University, Kenya, which made this communication possible. The authors commend preceding authors for their fruitful quest for knowledge on medicinal plants utilized by rural communities of East Africa, the reports of which the current study was based. Authors’ contributions SBO, AK, IK, EK, MPO, TO, and LB designed the study. SBO, IK, EK, MPO, TO, and LB performed literature search for medicinal plants in Uganda, Burundi, Rwanda, Kenya, Tanzania, and South Sudan, respectively. SBO and TO analyzed the collected data. TO, MPO, and LB verified the plant names in botanical databases and local languages. SBO, MPO, TO, and LB wrote the first draft of the manuscript. AK, IK, and EK reviewed the draft manuscript. All authors revised and approved the final manuscript. Funding This research received no external funding. Availability of data and materials This is a review article and no raw experimental data were collected. All data generated or analyzed during this study are included in this published article. Ethics approval and consent to participate Not applicable Consent for publication Not applicable Competing interests The authors declare that there is no conflict of interest regarding the publication of this paper. Author details 1 Department of Pharmacology and Therapeutics, Faculty of Health Sciences, Busitema University, P.O. Box 1460, Mbale, Uganda. 2Department of Chemistry and Biochemistry, School of Sciences and Aerospace Studies, Moi University, P.O. Box 3900-30100, Eldoret, Kenya. 3Africa Centre of Excellence II in Phytochemicals, Textiles and Renewable Energy (ACE II PTRE), Moi University, P.O. Box 3900-30100, Eldoret, Kenya. 4Department of Pure and Applied Chemistry, Faculty of Science, Masinde-Muliro University of Science and Technology, P.O. Box 190-50100, Kakamega, Kenya. 5Centre of Traditional Medicine and Drug Research, Kenya Medical Research Institute, P.O. Box 54840-00200, Nairobi, Kenya. 6Department of Quality Control and Quality Assurance, Product Development Directory, AgroWays Uganda Limited, Plot 34-60, Kyabazinga Way, P.O. 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