Zanthoxylum capense constituents with antimycobacterial activity against Mycobacterium tuberculosis in vitro and ex vivo within human macrophages

• Published in: Journal of ethnopharmacology 2013-03, Vol.146 (1), p.417-422
• Main Authors: Luo, Xuan, Pires, David, Aínsa, José A., Gracia, Begoña, Duarte, Noélia, Mulhovo, Silva, Anes, Elsa, Ferreira, Maria-José U.
• Format: Article
• Language: English
• Subjects: Antimycobacterial; Antitubercular Agents - pharmacology; Benzophenanthridine alkaloids; Cell Line; Cell Survival - drug effects; Humans; Macrophages - drug effects; Macrophages - microbiology; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - pathogenicity; N-isobutylamide; Plant Extracts - pharmacology; Plant Roots; Rutaceae; Tuberculosis; Tuberculosis - drug therapy; Zanthoxylum; Zanthoxylum capense
• ISSN: 0378-8741; 1872-7573
• DOI: 10.1016/j.jep.2013.01.013

Zanthoxylum capense Thunb. (Rutaceae) is a medicinal plant traditionally used in Mozambique to treat tuberculosis. The 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. By 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. The 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 1.6μg/ml), and a low macrophage cytotoxicity (IC50>60μg/ml), indicating considerable selective activity. The benzophenanthridine alkaloid 6-acetonyldihydronitidine (6) revealed cytotoxicity (IC50 1.7μg/ml), despite the determined MIC of 6.2–12.5μg/ml. In infected macrophages, decarine (1) was able to reduce bacterial survival by almost two log units at a concentration of 6.2μg/ml 5 days post-drug exposure. Compound 15 exhibited an intermediate activity at drug concentrations ranging from 6.2 to 25μg/ml. The 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. Decarine, isolated from the medicinal plant Zanthoxylum capense, showed high antimycobacterial activity in vitro and ex vivo and low cytotoxicity towards human macrophages. [Display omitted]