Tuberculosis (TB) is a major infectious disease associated increasingly with drug resistance. Thus, new anti-tubercular agents with novel mechanisms of action are urgently required for the treatment of drug-resistant TB. In prior work, we identified compound 1 (cyclohexyl(4-(isoquinolin-5-ylsulfonyl)piperazin-1-yl)methanone) and showed that its anti-tubercular activity is attributable to inhibition of inosine-5'-monophosphate dehydrogenase (IMPDH) in Mycobacterium tuberculosis. In the present study, we explored the structure-activity relationship around compound 1 by synthesizing and evaluating the inhibitory activity of analogues against M. tuberculosis IMPDH in biochemical and whole-cell assays. X-ray crystallography was performed to elucidate the mode of binding of selected analogues to IMPDH. We establish the importance of the cyclohexyl, piperazine and isoquinoline rings for activity, and report the identification of an analogue with IMPDH-selective activity against a mutant of M. tuberculosis that is highly resistant to compound 1. We also show that the nitrogen in urea analogues is required for anti-tubercular activity and identify benzylurea derivatives as promising inhibitors that warrant further investigation.

中文翻译：

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1-（5-异喹啉磺酰基）哌嗪类似物作为结核分枝杆菌IMPDH抑制剂的合成及其构效关系。

结核病（TB）是一种越来越多的与耐药性相关的主要传染病。因此，迫切需要具有新颖作用机制的新抗结核药来治疗耐药性TB。在先前的工作中，我们鉴定了化合物1（环己基（4-（异喹啉-5-基磺酰基）哌嗪-1-基）甲酮），并显示其抗结核活性可归因于肌苷5'-单磷酸脱氢酶（IMPDH）的抑制作用。 ）在结核分枝杆菌中。在本研究中，我们通过在生化和全细胞分析中合成和评估类似物对结核分枝杆菌IMPDH的抑制活性，探索了化合物1周围的构效关系。进行X射线晶体学分析以阐明所选类似物与IMPDH的结合方式。我们确定了环己基的重要性，