Synthesis, evaluation and mechanistic insights of novel IMPDH inhibitors targeting ESKAPEE bacteria

Ayoub, Nour; Upadhyay, Amit; Tête, Arnaud; Pietrancosta, Nicolas; Munier-Lehmann, Hélène; O'Sullivan, Timothy P.

Synthesis, evaluation and mechanistic insights of novel IMPDH inhibitors targeting ESKAPEE bacteria

dc.contributor.author	Ayoub, Nour	en
dc.contributor.author	Upadhyay, Amit	en
dc.contributor.author	Tête, Arnaud	en
dc.contributor.author	Pietrancosta, Nicolas	en
dc.contributor.author	Munier-Lehmann, Hélène	en
dc.contributor.author	O'Sullivan, Timothy P.	en
dc.contributor.funder	Irish Research Council	en
dc.contributor.funder	Science Foundation Ireland	en
dc.contributor.funder	Université Sorbonne Paris Cité	en
dc.date.accessioned	2024-11-11T14:58:00Z
dc.date.available	2024-11-11T14:58:00Z
dc.date.issued	2024-10-05	en
dc.description.abstract	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.	en
dc.description.sponsorship	Irish Research Council (GOIPG/2019/1117); Université Sorbonne Paris Cité (PhD fellowship MTCI, ED 563)	en
dc.description.status	Peer reviewed	en
dc.description.version	Published Version	en
dc.format.mimetype	application/pdf	en
dc.identifier.articleid	p.116920	en
dc.identifier.citation	Ayoub, N., Upadhyay, A., Tête, A., Pietrancosta, N., Munier-Lehmann, H. and O'Sullivan, T. P. (2024) 'Synthesis, evaluation and mechanistic insights of novel IMPDH inhibitors targeting ESKAPEE bacteria', European Journal of Medicinal Chemistry, 280, p.116920 (21pp). https://doi.org/10.1016/j.ejmech.2024.116920	en
dc.identifier.doi	https://doi.org/10.1016/j.ejmech.2024.116920	en
dc.identifier.endpage	21	en
dc.identifier.issn	0223-5234	en
dc.identifier.journaltitle	European Journal of Medicinal Chemistry	en
dc.identifier.startpage	1	en
dc.identifier.uri	https://hdl.handle.net/10468/16636
dc.identifier.volume	280	en
dc.language.iso	en	en
dc.publisher	Elsevier Ltd.	en
dc.relation.project	info:eu-repo/grantAgreement/SFI/SFI Research Infrastructure Programme/15/RI/3221/IE/Process Flow Spectroscopy (ProSpect); Advanced Reaction Understanding using Flow Nuclear Magnetic Resonance (NMR) and Infrared (IR) Spectroscopies, with On-Line Ultra-Performance Liquid Chromatography (UPLC) and Mass Spectrometry (MS)/	en
dc.rights	© 2024, The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)	en
dc.rights.uri	https://creativecommons.org/licenses/by/4.0/	en
dc.subject	Nucleotide metabolism	en
dc.subject	IMPDH	en
dc.subject	Inhibitors	en
dc.subject	Antibacterials	en
dc.subject	ESKAPEE bacteria	en
dc.subject	Heteroaryls	en
dc.title	Synthesis, evaluation and mechanistic insights of novel IMPDH inhibitors targeting ESKAPEE bacteria	en
dc.type	Article (peer-reviewed)	en
oaire.citation.volume	280	en