Design, synthesis and antimicrobial evaluation of 1,3,4- Oxadiazole/1,2,4-Triazole-Substituted thiophenes

Abstract

The increasing level of antimicrobial resistance in pathogenic bacteria, together with the lack of new potential drug scaffolds in the pipeline, make the problem of infectious diseases a major public health concern. Thus, in this context, a novel series of 1,3,4-oxadiazole-substituted thiophenes (4a–m) and 1,2,4-triazole (6a–m) substituted thiophene derivatives were synthesized. Characterization of all the synthesized derivatives was done by various spectroscopic techniques such as 1 HNMR, 13CNMR spectroscopy and mass spectrometry, and evaluated for antimicrobial activity against various pathological strains using broth dilution and disc diffusion method. In particular, compound 6e and 4e exhibited significant inhibitory potential with MIC ranging from 2–7 μg mL 1 against S. aureus, B. subtilis, P. aeruginosa and E. coli. Additionally, compound 6e was found to be highly potent against methicillin resistant S. aureus (MRSA; MIC=2 μgmL 1 ). Molecular docking studies were also performed to confer the possible mode of action and association studies indicate the binding of potent active compound with DHFR enzyme (Ka=2.10×103 M 1 ). Further, the mechanism of action has also been explored by atomic force microscopy (AFM), which reveals the bacterial cell wall deformity and cell wall rupturing that may lead to bacteria cell death. Additionally, in silico ADME prediction study suggested the drug like properties of active compoun