H3D Drug Discovery and Development Centre, Department of Drug Discovery and Development & Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, 7701, Cape Town, South Africa; MRC/NHLS/UCT Molecular Mycobacteriology Research Unit, DST/NRF Centre of Excellence for Biomedical TB Research & Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine & Department of Pathology, University of Cape Town, Anzio Road, Observatory, 7925, South Africa; South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, 7701, Cape Town, South Africa.
Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, United Kingdom.
Eur J Med Chem. 2019 Jul 15;174:309-329. doi: 10.1016/j.ejmech.2019.04.027. Epub 2019 Apr 15.
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.
结核病（TB）是一种与耐药性日益相关的主要传染病。因此，迫切需要具有新型作用机制的新型抗结核药物来治疗耐药性结核病。在之前的工作中，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），并表明其抗结核活性归因于分枝杆菌肌苷-5'-单磷酸脱氢酶（IMPDH）的抑制。在本研究中，我们通过合成和评估类似物对分枝杆菌 IMPDH 的生化和全细胞测定中的抑制活性，探索了化合物 1 周围的结构-活性关系。进行了 X 射线晶体学以阐明选定类似物与 IMPDH 的结合模式。我们确定了环己基、哌嗪和异喹啉环对活性的重要性，并报告了鉴定出的对高度耐受化合物 1 的结核分枝杆菌突变体具有 IMPDH 选择性活性的类似物。我们还表明，尿素类似物中的氮对于抗结核活性是必需的，并确定了苄基脲衍生物是有前途的抑制剂，值得进一步研究。
