Design, Synthesis, and Biological Evaluation of Indole-2-carboxamides: A Promising Class of Antituberculosis Agents
Design, Synthesis, and Biological Evaluation of Indole-2-carboxamides: A Promising Class of Antituberculosis Agents
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DOI：
10.1021/jm4012774
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发表时间：
2013-11-14
影响因子：
7.3
通讯作者：
Smith, Paul W.
中科院分区：
文献类型：
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作者：
Kondreddi, Ravinder Reddy;Jiricek, Jan;Smith, Paul W.
吲哚-2-甲酰胺类药物在抗结核分枝杆菌的表型筛选中被认为是一类很有前途的抗结核药物。其中一种命中物吲哚-2-甲酰胺类似物（1）对结核分枝杆菌（Mtb）的微摩尔效力较低，小鼠肝微粒体清除率较高，水溶性较低。构效关系的研究表明，连接的烷基基团的环己基环显着提高Mtb的活性，但降低了溶解度。此外，吲哚环的4-和6-位上的氯、氟或氰基取代以及环己基环上的甲基取代显著改善了代谢稳定性。39和41，主要候选药物，与目前大多数标准结核病药物相比，显示出改善的体外活性。由于亲脂性与Mtb效力正相关，因此不能减轻低水溶性。然而，这两种化合物在啮齿动物中显示出良好的口服药代动力学特性，并证明了体内疗效。因此，吲哚-2-甲酰胺类药物是一类很有前途的新型抗结核药物。
Indole-2-carboxamides have been identified as a promising class of antituberculosis agents from phenotypic screening against mycobacteria. One of the hits, indole-2-carboxamide analog (1), had low micromolar potency against Mycobacterium tuberculosis (Mtb), high mouse liver microsomal clearance, and low aqueous solubility. Structure activity relationship studies revealed that attaching alkyl groups to the cyclohexyl ring significantly improved Mtb activity but reduced solubility. Furthermore, chloro, fluor, or cyano substitutions on the 4- and 6-positions of the indole ring as well as methyl substitution on the cyclohexyl ring significantly improved metabolic stability. 39 and 41, the lead candidates, displayed improved in vitro activity compared to most of the current standard TB drugs. The low aqueous solubility could not be mitigated because of the positive correlation of lipophilicity with Mtb potency. However, both compounds displayed favorable oral pharmacokinetic properties in rodents and demonstrated in vivo efficacy. Thus, indole-2-carboxamides represent a promising new class of antituberculosis agents.