Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, Singapore 138670.
J Med Chem. 2013 Nov 14;56(21):8849-59. doi: 10.1021/jm4012774. Epub 2013 Oct 22.
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, fluoro, 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.
吲哚-2-甲酰胺类化合物已被鉴定为从分枝杆菌表型筛选中具有潜在抗结核作用的一类化合物。其中一个命中化合物，吲哚-2-甲酰胺类似物（1）对结核分枝杆菌（Mtb）具有低微摩尔效力，高小鼠肝微粒体清除率和低水溶解度。构效关系研究表明，将烷基基团连接到环己基环上可显著提高 Mtb 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上的甲基取代显著提高了代谢稳定性。39 和 41 作为先导候选物，与大多数当前的标准 TB 药物相比，显示出改善的体外活性。由于亲脂性与 Mtb 效力呈正相关，因此无法减轻低水溶解度的问题。然而，这两种化合物在啮齿动物中均表现出良好的口服药代动力学特性，并显示出体内疗效。因此，吲哚-2-甲酰胺类化合物代表了一类有前途的新型抗结核药物。
