Synthesis and Design of New 1,3,4‐Oxadiazole Benzimidazole Hybrids as Potential Antibacterial Agents Against MRSA by Targeting FabI

Abstract The current investigation describes the synthesis of the 1,3,4‐oxadiazole benzimidazole hybrids 5 (a–m) as antibacterial agents against methicillin‐resistant Staphylococcus aureus (MRSA) by targeting the enoyl‐acyl carrier protein binding site of enoyl‐acyl carrier protein reductase (FabI). Compounds having better (2–6 µg/mL) minimum inhibitory concentrations (MIC) than ampicillin (100 µg/mL) in initial screening using the broth dilution method against S. aureus ( ATCC ‐29213) were further gauged for their antimicrobial potential against MRSA (ATCC 4330) using sultamicillin as a standard. 5‐(2‐(4‐Chlorophenyl)‐1 H ‐benzo[d]imidazol‐6‐yl)‐ N ‐phenyl‐1,3,4‐oxadiazol‐2‐amine ( 5a ) was found to be most potent against MRSA with a MIC of 6 µg/mL in comparison to sultamicillin (25 µg/mL). Furthermore, the time‐kill assay exhibited that compound 5a was bactericidal and demonstrated a high safety profile, as hemolysis caused in human red blood cells was insignificant (1.6%) at the concentration of 6 µg/mL (MIC × 3). To establish the molecular target of action, in silico molecular docking studies were performed against Sa FabI to reconnoiter the intervention of the molecules in the FAS‐II pathway. Compound 5a exhibited high binding affinity (−11.19) to the target; furthermore, the molecular dynamic simulation studies affirmed the stability of compound 5a , within the active site of the target. All compounds exhibited drug‐appropriate physicochemical characteristics and pharmacokinetic profiles as established by computational ADMET analysis. The study revealed that the synthesized library of small‐molecule oxadiazole benzimidazole hybrids holds promise for developing new antibacterial agents against MRSA infections.