Design, Microwave‐Assisted Synthesis, and Biological Evaluation of Novel 1,3‐Thiazolidin‐4‐One Hybrids: Insights From DFT, Molecular Docking, and ADMET Profiling

A highly efficient, environmentally benign one-pot multicomponent protocol was developed for synthesizing novel 1,3-thiazolidin-4-one derivatives via microwave irradiation of 3-pyridyl isothiocyanate, primary amines, and ethyl chloroacetate. This green methodology delivered 3-substituted-2-(pyridin-3-ylimino)thiazolidin-4-ones in 2-5 min (66%-81% yields), representing a dramatic improvement over conventional reflux (3-6 h). All structures were unambiguously characterized by FT-IR, NMR spectroscopy, and elemental analysis. Antibacterial screening against Gram-positive (Bacillus cereus, Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa, Escherichia coli) pathogens revealed exceptional potency, particularly for the 3-chlorophenyl derivative (8), which achieved 82% of ciprofloxacin's activity against E. coli (45 mm inhibition zone). Structure-activity relationships demonstrated that aromatic N-substituents with electron-withdrawing groups significantly enhanced antimicrobial efficacy through π-conjugation and σ-hole interactions. Comprehensive computational studies (FMO analysis, ADMET profiling, and molecular docking against DNA gyrase subunit B) validated the experimental findings, revealing that compound 8 forms robust halogen-bonded and π-stacked complexes, acting as an allosteric inhibitor. With excellent drug-likeness (QED = 0.777-0.913), low toxicity risks, and a favorable therapeutic window, this scaffold offers a promising platform for developing next-generation antibacterial agents targeting resistant bacterial strains.