Design, synthesis and computational approach of vanillyl-imidazolonyl-sulfamethoxazole derivatives as potent antimicrobial candidates tackling microbial resistance

Abstract

Superbugs are dominating the world due to misuse and overuse of the antibiotics. In the queue of design and synthesising new molecules with increased efficacy and capability to tackle microbial resistance, two sets of compounds oxazolones (3a-3j) and their respective imidazolones (4a-4j) bearing sulfonamide functional group were synthesized. The compounds structural conformation was done using different techniques like 1H/13C NMR, FT-IR, HRMS and elemental analysis. The binding affinity on specific targets of these congeners were predicted through molecular docking. The docking results indicated that the compound 4j (-10.36 kcal/mol) and 4g (-8.62 kcal/mol) had shown minimum binding energy with strong affinity against target penicillin binding protein 2a of methicillin resistance S. aureus (MRSA) and C14α-demethylase (CYP51) of C. albicans respectively. Further, these compounds were investigated for their antimicrobial efficacies, results among which the imidazolones derived compounds 4d and 4g had shown significant inhibition than Gentamicin in-terms of zone of inhibition and MIC value. However, the oxazolone derived compound 3i had shown the maximum zone of inhibition of 20 mm against MDR T. rubrum strain which is comparably better inhibition than Ketoconazole. Following these finding, HOMO-LUMO analysis was carried out and the compound 4g had shown the smallest energy gap of 3.15 eV. For antibacterial activity of imidazolones are more effective than oxazolones, whereas for fungal strains the action has been reversed. To combat against resistant pathogens multifaced treatments should be followed and compounds like 4d and 4g might play a significant role in that. The synthetic as well as biological outcome of the newer vanillyl-imidazolonyl-sulfamethoxazole derivatives mark a footstep onto the drug discovery pipeline in bacterial resistance era.