Structure-activity relationships of antitubercular salicylanilides consistent with disruption of the proton gradient via proton shuttling
Structure-activity relationships of antitubercular salicylanilides consistent with disruption of the proton gradient via proton shuttling
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DOI：
10.1016/j.bmc.2012.10.056
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发表时间：
2013-01-01
影响因子：
3.5
通讯作者：
Barry, Clifton E., III
中科院分区：
文献类型：
--
作者：
Lee, Ill-Young;Gruber, Todd D.;Barry, Clifton E., III
基于结核分枝杆菌的高通量筛选，合成了一系列水杨酰苯胺类化合物。活性需要水杨酸部分上的游离酚羟基，并且苯胺环的结构-活性关系在很大程度上由吸电子基团的存在驱动。我们合成了94个类似物，探索了这一系列中两个环和接头区域的取代，并且我们已经鉴定了多种具有低微摩尔效力的化合物。不幸的是，在鼠巨噬细胞系中的细胞毒性倾向于抗微生物活性，表明类似的作用机制。我们认为水杨酰苯胺作为质子穿梭剂，通过破坏细胞质子梯度来杀死细胞，限制了它们作为潜在治疗剂的效用。由爱思唯尔有限公司发布
A series of salicylanilides was synthesized based on a high-throughput screening hit against Mycobacterium tuberculosis. A free phenolic hydroxyl on the salicylic acid moeity is required for activity, and the structure-activity relationship of the aniline ring is largely driven by the presence of electron withdrawing groups. We synthesized 94 analogs exploring substitutions of both rings and the linker region in this series and we have identified multiple compounds with low micromolar potency. Unfortunately, cytotoxicity in a murine macrophage cell line trends with antimicrobial activity, suggesting a similar mechanism of action. We propose that salicylanilides function as proton shuttles that kill cells by destroying the cellular proton gradient, limiting their utility as potential therapeutics. Published by Elsevier Ltd.