Novel 1,3,4-thiadiazole cephalosporin derivatives as potential antibacterial agents. Chemical synthesis, biological evaluation, and computational study

1,3,4-Thiadiazole cephalosporin derivs. were designed and synthesized as potential cephalosporin-based antibacterial agents. The synthesized compds. were evaluated in vitro for antibacterial activity against Gram-positive (S. aureus, S. pneumoniae) and Gram-negative (P. aeruginosa, K. pneumoniae, E. coli) pathogens. Biol. assays demonstrated that all derivs. exhibited broad-spectrum antibacterial efficacy, comparable or outperforming reference drugs in comparative analyses. Notably, the compd. 17i displayed the most potent activity across tested strains. Mol. docking studies revealed that 17i formed stable interactions at both the active site and allosteric pocket of penicillin-binding protein 2a (PBP2a) from methicillin-resistant S. aureus (MRSA, PDB: 3ZG0), suggesting a dual-binding mechanism. Addnl., in silico predictions of pharmacokinetic properties ADMET (absorption, distribution, metabolism, excretion, and toxicity) and mol. characteristics indicated favorable drug-like profiles for selected derivs., highlighting their potential as candidates for further development against multi-drug-resistant infections.