Université Paris Cité, INSERM UMRS-1124, Institut Pasteur, Structural Biology and Chemistry Department, F-75006, Paris, France.
School of Chemistry, University College Cork, Cork, Ireland; School of Pharmacy, University College Cork, Cork, Ireland; Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland.
Eur J Med Chem. 2024 Dec 15;280:116920. doi: 10.1016/j.ejmech.2024.116920. Epub 2024 Sep 27.
Antimicrobial resistance poses a significant threat to global health, necessitating the development of novel therapeutic agents with unique mechanisms of action. Inosine 5'-monophosphate dehydrogenase (IMPDH), an essential enzyme in guanine nucleotide biosynthesis, is a promising target for the discovery of new antimicrobial agents. High-throughput screening studies have previously identified several urea-based leads as potential inhibitors, although many of these are characterised by reduced chemical stability. In this work, we describe the design and synthesis of a series of heteroaryl-susbtituted analogues and the evaluation of their inhibitory potency against IMPDHs. Our screening targets ESKAPEE pathogens, including Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli. Several analogues with submicromolar inhibitory potency are identified and show no inhibitory potency on human IMPDH nor cytotoxic effects on human cells. Kinetic studies revealed that these molecules act as noncompetitive inhibitors with respect to the substrates and ligand virtual docking simulations provided insights into the binding interactions at the interface of the NAD and IMP binding sites on IMPDH.
抗菌药物耐药性对全球健康构成重大威胁，因此需要开发具有独特作用机制的新型治疗药物。肌苷 5'-单磷酸脱氢酶（IMPDH）是鸟嘌呤核苷酸合成中的一种必需酶，是发现新型抗菌药物的有前途的靶标。先前的高通量筛选研究已经确定了几种基于尿素的先导化合物作为潜在抑制剂，尽管其中许多化合物的化学稳定性降低。在这项工作中，我们描述了一系列杂芳基取代类似物的设计和合成，并评估了它们对 IMPDH 的抑制活性。我们的筛选靶标包括 ESKAPEE 病原体，包括铜绿假单胞菌、金黄色葡萄球菌和大肠杆菌。鉴定出几种具有亚微摩尔抑制活性的类似物，它们对人 IMPDH 没有抑制活性，对人细胞也没有细胞毒性作用。动力学研究表明，这些分子作为非竞争性抑制剂与底物相互作用，虚拟对接模拟提供了 IMPDH 上 NAD 和 IMP 结合位点界面结合相互作用的见解。
