Zanthoxylum capense constituents with antimycobacterial activity against Mycobacterium tuberculosis in vitro and ex vivo within human macrophages |
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Authors: | Xuan Luo David Pires José A Aínsa Begoña Gracia Noélia Duarte Silva Mulhovo Elsa Anes Maria-José U Ferreira |
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Institution: | 1. Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal;2. Centro de Patogénese Molecular, Unidade dos Retrovírus e Infecções Associadas e Instituto de Medicina Molecular, Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal;3. Department of Microbiology, Faculty of Medicine, University of Zaragoza, C/ Domingo Miral s/n, 50009 Zaragoza, Spain;4. CIBER Enfermedades Respiratorias (CIBERES), Spain;5. Centro de Estudos Moçambicanos e de Etnociências, Universidade Pedagógica Campus de Lhanguene, Av. de Moçambique, 21402161 Maputo, Mozambique |
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Abstract: | Ethnopharmacological relevanceZanthoxylum capense Thunb. (Rutaceae) is a medicinal plant traditionally used in Mozambique to treat tuberculosis.Aims of the studyThe main aim of the study was to find antimycobacterial lead compounds from Zanthoxylum capense. Another goal was to provide scientific validation for the use of this plant in traditional medicine.Methods and materialsBy bioassay-guided fractionation, 16 compounds were isolated and screened for their in vitro antimycobacterial activity against two different strains of Mycobacterium tuberculosis. Their in vitro cytotoxicity to human THP-1 macrophages was also assessed. The compounds with favourable selectivity index values (SI>10) were further investigated for their ability to inhibit the growth of Mycobacterium tuberculosis H37Rv in an intracellular macrophage model of infection.ResultsThe best results were obtained for a benzophenanthridine alkaloid, decarine (1), and an N-isobutylamide, N-isobutyl-(2E,4E)-2,4-tetradecadienamide (15), which showed high activity against Mycobacterium tuberculosis H37Rv (MIC of 1.6 μg/ml), and a low macrophage cytotoxicity (IC50>60 μg/ml), indicating considerable selective activity. The benzophenanthridine alkaloid 6-acetonyldihydronitidine (6) revealed cytotoxicity (IC50 1.7 μg/ml), despite the determined MIC of 6.2–12.5 μg/ml. In infected macrophages, decarine (1) was able to reduce bacterial survival by almost two log units at a concentration of 6.2 μg/ml 5 days post-drug exposure. Compound 15 exhibited an intermediate activity at drug concentrations ranging from 6.2 to 25 μg/ml.ConclusionsThe high antimycobacterial activity of decarine found, both in vitro and ex vivo against mycobacteria, and the low cytotoxicity towards human macrophages indicate that it may be valuable as a lead scaffold for the development of anti-TB drugs. |
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Keywords: | Antimycobacterial Benzophenanthridine alkaloids N-isobutylamide Tuberculosis Zanthoxylum capense |
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