Contributors: Département de Biologie structurale et Chimie - Department of Structural Biology and Chemistry; Institut Pasteur Paris (IP)-Université Paris Cité (UPCité); Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124); Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité); University College Cork (UCC); Analyse, Interactions Moléculaires et Cellulaires (LBM-E2); Laboratoire des biomolécules (LBM UMR 7203); Chimie Moléculaire de Paris Centre (FR 2769); École normale supérieure - Paris (ENS-PSL); Université Paris Sciences et Lettres (PSL)-Université Paris Sciences et Lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP); Université Paris Sciences et Lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris); Université Paris Sciences et Lettres (PSL)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL); Université Paris Sciences et Lettres (PSL)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris; Université Paris Sciences et Lettres (PSL)-Université Paris Sciences et Lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Chimie Moléculaire de Paris Centre (FR 2769); Université Paris Sciences et Lettres (PSL)-Université Paris Sciences et Lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); Neuroscience Paris Seine (NPS); Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS); Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS); Amit Upadhyay is grateful for funding by way of a Government of Ireland Postgraduate Research Scholarship (GOIPG/2019/1117) pro- vided by the Irish Research Council.; Nour Ayoub acknowledges a PhD fellowship from Médicament, Toxicologie, Chimie et Imagerie PhD school (MTCI, ED 563), Université Paris Cité.; This work was undertaken using equipment provided by Science Foundation Ireland though a research infrastructure award for process flow spectroscopy (ProSpect) (SFI 15/ RI/3221).; Some of the antimicrobial screening was performed by CO-ADD (The Community for Antimicrobial Drug Dis- covery), funded by the Wellcome Trust (UK) and The University of Queensland (Australia).
نبذة مختصرة : International audience ; 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.
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