Abstract
BackgroundTwo 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.MethodsA 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.ResultsIn 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).ConclusionCompound 8b provides a lead compound for further structural development to obtain high affinity PheRS inhibitors.
Highlights
Antimicrobial resistance is one of the most challenging medical dilemmas worldwide [1,2,3,4]
Computational studies The designed compounds were examined for their conformational similarity with the natural phenylalanyl-tRNA synthetase (PheRS) substrate Phenylalanyl adenylate (Phe-AMP) using the flexible alignment tool in Molecular Operating Environment (MOE) [31]
The benzimidazole moiety in the designed scaffold overlaps with the adenine moiety of Phe-AMP, and both the oxadiazole and thiadiazole moieties overlap with the phosphate group of the natural substrate, while the terminal aromatic moiety aligns with the phenylalanine aromatic ring
Summary
Antimicrobial resistance is one of the most challenging medical dilemmas worldwide [1,2,3,4]. Bacterial cells have exceptional survival genetic plasticity mechanisms that are highly flexible in encountering environmental threats [7], efforts should be focused on decreasing antimicrobial resistance development. Improper and over prescription of broad-spectrum antibiotics are the Noureldin et al BMC Chemistry (2021) 15:58 main causes that exert a high pressure enhancing the natural genetic mutations in pathogenic bacteria [1]. Finding new targets within the bacterial cells is considered a promising strategy to overcome the high rates of antimicrobial resistance development. 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
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