Design, synthesis and evaluation of indole-2-carboxamides with pan anti-mycobacterial activity
Design, synthesis and evaluation of indole-2-carboxamides with pan anti-mycobacterial activity
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DOI：
10.1016/j.bmc.2017.05.015
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发表时间：
2017-07-15
影响因子：
3.5
通讯作者：
North, E. Jeffrey
中科院分区：
文献类型：
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作者：
Franz, Nicholas D.;Belardinelli, Juan Manuel;North, E. Jeffrey
目前治疗非结核分枝杆菌(NTM)和结核病(TB)的治疗方案通常需要使用多种药物进行长时间的治疗，其中一些是广谱抗生素。尽管在抗菌化合物方面取得了一些进展，但仍然需要针对特定分枝杆菌靶点的抗生素进行治疗。已有研究表明，MmpL3是将霉菌酸转运到分枝杆菌细胞膜上所必需的转运蛋白。在这里，我们合成了一系列吲哚2-羧胺类化合物，它们能抑制MmpL3，并具有很强的抗分枝杆菌活性。这些化合物对几种快速和缓慢生长的分枝杆菌进行了测试，包括脓肿分枝杆菌、马氏分枝杆菌、博莱蒂分枝杆菌、龟分枝杆菌、结核分枝杆菌、禽类分枝杆菌、Xenopi分枝杆菌和耻垢分枝杆菌。这些基于吲哚的化合物的靶标使它们对分枝杆菌具有选择性，而对金黄色葡萄球菌或铜绿假单胞菌没有临床相关的杀菌活性。这些化合物对人类细胞株THP-1进行了测试，显示出最低的体外细胞毒性和良好的选择性指数。显示和讨论的数据表明，吲哚-2-羧胺铅是作为NTM治疗药物进行进一步临床前试验的有力竞争者。(C)2017爱思唯尔有限公司。保留所有权利。
Current treatment regimens for non-tuberculous mycobacteria (NTM) and tuberculosis (TB) generally require long duration of therapy with multiple drugs, some of which are broad spectrum antibiotics. Despite some advances in antimicrobial compounds, there remains a need in therapy for antibiotics with specific mycobacterial targets. It has been shown that MmpL3 is an essential transporter required for the translocation of mycolic acids to the mycobacterial cell envelope. Here, we synthesized a series of indole2-carboxamides that inhibit MmpL3 and have potent pan-activity against mycobacterial species. The compounds were tested against several fast and slow-growing Mycobacterium species, including M. abscessus, M. massiliense, M. bolletii, M. chelonae, M. tuberculosis, M. avium, M. xenopi and M. smegmatis. The target of these indole-based compounds makes them selective for mycobacteria, while showing no clinically relevant bactericidal activity against S. aureus or P. aeruginosa. These compounds were tested against THP-1, a human-cell line, and showed minimal in vitro cytotoxicity and good selectivity indices. The data shown and discussed suggest that lead indole-2-carboxamides are strong contenders for further preclinical testing as NTM therapeutics. (C) 2017 Elsevier Ltd. All rights reserved.