TY - JOUR
T1 - Zanthoxylum capense constituents with antimycobacterial activity against Mycobacterium tuberculosis in vitro and ex vivo within human macrophages
AU - Luo, Xuan
AU - Pires, David
AU - Aínsa, José A.
AU - Gracia, Begoña
AU - Duarte, Noélia
AU - Mulhovo, Silva
AU - Anes, Elsa
AU - Ferreira, Maria José U.
N1 - Funding Information:
This study was supported by the Portuguese Foundation for Science and Technology (FCT) (Grant nos. BPD/37179/2007 ; PEst-OE/SAU/UI4013/2011 and PTDC/SAU- MII/098024/2008) . The authors thank Dr. Catarina Arruda and Dr. Isabel Pestana, from the Portuguese Embassy in Mozambique, as well as the Portuguese Office of International Affairs for plant transport. We thank Dessi Marinova for helpful comments on the manuscript.
PY - 2013/3/7
Y1 - 2013/3/7
N2 - Ethnopharmacological relevance: Zanthoxylum capense Thunb. (Rutaceae) is a medicinal plant traditionally used in Mozambique to treat tuberculosis. Aims of the study: 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. Methods and materials: 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. Results: 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 1.6 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. Conclusions: 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.
AB - Ethnopharmacological relevance: Zanthoxylum capense Thunb. (Rutaceae) is a medicinal plant traditionally used in Mozambique to treat tuberculosis. Aims of the study: 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. Methods and materials: 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. Results: 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 1.6 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. Conclusions: 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.
KW - Antimycobacterial
KW - Benzophenanthridine alkaloids
KW - N-isobutylamide
KW - Tuberculosis
KW - Zanthoxylum capense
UR - http://www.scopus.com/inward/record.url?scp=84874112005&partnerID=8YFLogxK
U2 - 10.1016/j.jep.2013.01.013
DO - 10.1016/j.jep.2013.01.013
M3 - Article
C2 - 23337743
AN - SCOPUS:84874112005
SN - 0378-8741
VL - 146
SP - 417
EP - 422
JO - Journal of Ethnopharmacology
JF - Journal of Ethnopharmacology
IS - 1
ER -