Design, computational studies, synthesis and in vitro antimicrobial evaluation of benzimidazole based thio-oxadiazole and thio-thiadiazole analogues

Noureldin, Nada A., Richards, Jennifer, Kothayer, Hend, Baraka, Mohammed M., Eladl, Sobhy M., Wootton, Mandy and Simons, Claire ORCID: https://orcid.org/0000-0002-9487-1100 2021. Design, computational studies, synthesis and in vitro antimicrobial evaluation of benzimidazole based thio-oxadiazole and thio-thiadiazole analogues. BMC Chemistry 15 (1) , 58. 10.1186/s13065-021-00785-8

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Abstract

Background Two series of benzimidazole based thio-oxadiazole and thio-thiadiazole analogues were designed and synthesised as novel antimicrobial drugs through inhibition of phenylalanyl-tRNA synthetase (PheRS), which is a promising antimicrobial target. Compounds were designed to mimic the structural features of phenylalanyl adenylate (Phe-AMP) the PheRS natural substrate. Methods A 3D conformational alignment for the designed compounds and the PheRS natural substrate revealed a high level of conformational similarity, and a molecular docking study indicated the ability of the designed compounds to occupy both Phe-AMP binding pockets. A molecular dynamics (MD) simulation comparative study was performed to understand the binding interactions with PheRS from different bacterial microorganisms. The synthetic pathway of the designed compounds proceeded in five steps starting from benzimidazole. The fourteen synthesised compounds 5a-d, 6a-c, 8a-d and 9a-c were purified, fully characterised and obtained in high yield. Results In vitro antimicrobial evaluation against five bacterial strains showed a moderate activity of compound 8b with MIC value of 32 μg/mL against S. aureus, while all the synthesised compounds showed weak activity against both E. faecalis and P. aeruginosa (MIC 128 μg/mL). Conclusion Compound 8b provides a lead compound for further structural development to obtain high affinity PheRS inhibitors.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Advanced Research Computing @ Cardiff (ARCCA) Pharmacy
Additional Information:	This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.
Publisher:	Bio Med Central
ISSN:	2661-801X
Date of First Compliant Deposit:	8 November 2021
Date of Acceptance:	20 October 2021
Last Modified:	12 Jul 2024 16:05
URI:	https://orca.cardiff.ac.uk/id/eprint/145359

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