Exploring Oxazolidinone scaffolds for future antibiotics: synthesis and computational insights with DFT, docking, ADME and MD simulation

Abstract

The emergence of antibiotic-resistance is a serious concern in maintaining global health in this era, which necessitates constant advancements in antibacterial research for effective antibacterial solutions. To address this issue, a series of oxazolidinone derivatives bearing biologically significant functionalities were efficiently synthesized and screened for in vitro antimicrobial activities against four bacterial strains viz. two Gram positive strains: S. aureus, S. pyogenes, two Gram negative strains: E. coli, P. aeruginosa, and two fungal strains namely, C. albicans, A. niger, in comparison to standard drugs like Ampicillin and Nystatin, respectively. Further, DFT study were performed and these compounds were screened for their binding efficacies against the respective target proteins, followed by prediction of drug-likeness and ADME properties. Among the oxazolidinone derivatives, compounds 7 g and 7i display excellent activity. Interestingly, 7 g emerged as a promising candidate, demonstrating better effectiveness against E. coli (12 µg/mL), P. aeruginosa (20 µg/mL) and S. aureus (50 µg/mL) compared to reference drug Ampicillin. Compound 7a exhibited excellent activity against A. niger and C. albicans with an MIC of 50 µg/mL and 100 µg/mL compared to Nystatin (MIC = 100 µg/mL). Molecular Dynamics simulations were performed on the target protein for 7 g, demonstrating exceptional biological activity and binding affinity in in silico studies. These results suggest that oxazolidinone derivative 7 g, 7i and 7k is a promising therapeutic candidate for drug-resistant bacterial and fungal infections.

Graphical abstract