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Conformational study into alkyl-aryl ureas to inform drug discovery

Lookup NU author(s): Dr Hannah Stewart, Dr Mathew Martin, Lan Wang, Dr Eilidh Mackenzie, Professor Mike Waring



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Ureas are an important functional group in small molecule drugs as well as having wider applications in organic chemistry. Understanding of their conformation is of critical importance for rational design of urea-containing bioactive compounds. Whilst the conformational preferences of biaryl ureas have been extensively studied, very little attention has been paid to alkylated analogues. We carried out a systematic study of N-aryl (phenyl and pyridyl)-N’-cyclopentyl ureas with differing N-methylation patterns using Well Tempered Metadynamics at a semi-empirical level in implicit water (GBSA) using Well-Tempered Metadynamics to generate their conformational free-energy landscapes. Geometries and energetics of the most relevant configurations are further refined using DFT level of theory. Validation for the computation was obtained by synthesis of all 8 analogues followed by conformational studies by X-ray crystallography and NMR. These findings reveal that the methylation pattern significantly affects the conformational preference of the system. Most notably, N-phenyl-N’-cyclopentyl urea is shown to adopt both the trans-trans, and cis-trans conformations with equal energy and that the cis-trans conformation can be significantly stabilised by the presence of an internal hydrogen bond to the N’-hydrogen. This study will be of utility for the design of N-alkyl-N’-aryl ureas as drug candidates.

Publication metadata

Author(s): Stewart HL, Bon M, Wills C, Martin MP, Wang L, Mackenzie ES, Wadell PG, Waring MJ

Publication type: Article

Publication status: Published

Journal: Bioorganic and Medicinal Chemistry

Year: 2023

Volume: 91

Online publication date: 15/08/2023

Acceptance date: 19/06/2023

Date deposited: 20/06/2023

ISSN (print): 0968-0896

ISSN (electronic): 1464-3391

Publisher: Elseiver


DOI: 10.1016/j.bmc.2023.117387


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