Design, synthesis, biological evaluation, and in silico studies of thiazole-based alkyl ester derivatives as potential antimicrobial agents

A novel series of thiazole-based alkyl ester derivatives ( 3a–3h ) was rationally designed, synthesized, and evaluated for their antimicrobial, antioxidant, and in silico pharmacological properties. The target compounds were synthesized through esterification of 2-(4-(benzyloxy)-3-cyanophenyl)-4-methylthiazole-5-carboxylic acid ( 1 ) and structurally characterized using FT-IR, 1 H NMR, 13 C NMR, and mass spectrometry. The antimicrobial activities were evaluated against Gram-negative ( Escherichia coli and Pseudomonas aeruginosa ), Gram-positive ( Bacillus megaterium and Staphylococcus aureus ), and fungal strains ( Aspergillus niger , Aspergillus oryzae , Rhizopus sp., and Candida albicans ). Among the synthesized derivatives, compounds 3a , 3d , and 3f exhibited the most promising antimicrobial profiles, while several compounds also demonstrated appreciable antioxidant activity with minimal hemolytic toxicity. Structure–activity relationship analysis indicated that appropriate ester substitution and balanced lipophilicity contributed significantly to the observed biological activity. Molecular docking studies against DNA gyrase B (PDB ID: 6F86) and lanosterol 14α-demethylase (CYP51; PDB ID: 4UYL) revealed favorable binding interactions, and the docking protocol was validated by re-docking the co-crystallized ligands, yielding RMSD values below 2.0 Å, thereby confirming the reliability of the docking methodology. In addition, Ramachandran plot analysis demonstrated the stereochemical quality of both protein structures. In silico ADMET predictions suggested favorable oral drug-like properties for most compounds, although the predicted inhibition of multiple CYP450 isoforms indicates the need for further pharmacokinetic optimization and experimental validation. Overall, these findings identify thiazole-based alkyl ester derivatives as promising lead molecules for the development of new antimicrobial agents and provide a foundation for further structural optimization and biological investigation.