The enzyme Zmp1 is a zinc‐containing peptidase that plays a critical role in the pathogenicity of Mycobacterium tuberculosis. Herein we describe the identification of a small set of Zmp1 inhibitors based on a novel 8‐hydroxyquinoline‐2‐hydroxamate scaffold. Among the synthesized compounds, N‐(benzyloxy)‐8‐hydroxyquinoline‐2‐carboxamide (1 c) was found to be the most potent Zmp1 inhibitor known to date, and its binding mode was analyzed both by kinetics studies and molecular modeling, identifying critical interactions of 1 c with the zinc ion and residues in the active site. The effect of 1 c on intracellular Mycobacterium survival was assayed in J774 murine macrophages infected with M. tuberculosis H37Rv or M. bovis BCG and human monocyte‐derived macrophages infected with M. tuberculosis H37Rv. Cytotoxicity and genotoxicity were also assessed. Overall, inhibitor 1 c displays interesting in vitro antitubercular properties worthy of further investigation.

中文翻译：

---

结核分枝杆菌毒力因子Zmp1的强效抑制剂的开发及其对巨噬细胞内分枝杆菌存活的影响的评价

Zmp1酶是一种含锌的肽酶，在结核分枝杆菌的致病性中起关键作用。在本文中，我们描述了基于新型8-羟基喹啉-2-异羟肟酸酯支架的一小套Zmp1抑制剂的鉴定。在合成的化合物中，N-（苄氧基）-8-羟基喹啉-2-羧酰胺（1 c）被发现是迄今已知最有效的Zmp1抑制剂，并通过动力学研究和分子模型分析了其结合模式，1 c与锌离子和活性位点中的残基之间的关键相互作用。的效果1c中对细胞内分枝杆菌存活率分析在感染了J774小鼠巨噬细胞的结核分枝杆菌H37Rv的或牛分枝杆菌BCG和感染人单核细胞源性巨噬细胞的结核分枝杆菌H37Rv的。还评估了细胞毒性和遗传毒性。总体而言，抑制剂1c表现出有趣的体外抗结核特性，值得进一步研究。