期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 125, 期 -, 页码 1088-1097出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.10.055
关键词
Trypanosoma cruzi; Trypanothione; Nitroheterocycle drugs; Nifurtimox
资金
- UNL (CAI+D'11)
- CONICET [PIP112-2011-0100439, PIP114-2011-0100168, PIP GI 112-200801-00796]
- ANPCyT [PICT-2014-3256]
- UNR [1BIO303 19/B450]
The rational design and synthesis of a series of 5-nitro-2-furoic acid analogues are presented. The trypanocidal activity against epimastigote forms of Trypanosoma cruzi and the toxic effects on human HeLa cells were tested. Between all synthetic compounds, three of thirteen had an IC50 value in the range of Nfx, but compound 13 exhibited an improved effect with an IC50 of 1.0 +/- 0.1 mu M and a selective index of 70 in its toxicity against HeLa cells. We analyzed the activity of compounds 8,12 and 13 to interfere in the central redox metabolic pathway in trypanosomatids, which is dependent of reduced trypanothione as the major pivotal thiol. The three compounds behaved as better inhibitors of trypanothione reductase than Nfx (Ki values of 118 mu M, 61 mu M and 68 mu M for 8,12 and 13, respectively, compared with 245 mu M for Nfx), all following an uncompetitive enzyme inhibition pattern. Docking analysis predicted a binding of inhibitors to the enzyme-substrate complex with binding energy calculated in-silico that supports such molecular interaction. (C) 2016 Elsevier Masson SAS. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据