Synthesis, spectroscopic characterization, and exploration of the antimicrobial potential of thiophene-linked 2-(2-hydrazinyl)thiazole scaffolds: a DFT study, molecular docking analysis, and ADME evaluation

Abstract

In this study, we report the synthesis, structural characterization, computational analysis, and antimicrobial evaluation of 2-(2-hydrazinyl)thiazole derivatives. Structural elucidation was accomplished using FT-IR, ¹H NMR, and ¹³C NMR spectroscopy, while Density Functional Theory (DFT) calculations at the B3LYP/6-311G(d,p) level provided insights into optimized geometries, electronic properties, and global reactivity descriptors. Antimicrobial screening revealed notable antifungal activity for compounds 4d, 4f, and 4g, with compound 4g exhibiting superior inhibition against Candida albicans and displaying a low MIC value. Molecular docking studies against sterol 14-α-demethylase (CYP51) demonstrated strong binding of compound 4g within the enzyme active site, yielding a favorable docking score of −8.1 kcal/mol. The binding of compound 4g stabilized by π – cation interaction, π – π interactions, π – sulfur interactions, and extensive hydrophobic contacts, supporting its potent antifungal activity. Electronic structure analysis showed HOMO – LUMO energy gaps in the range of 3.06–3.79 eV, with compound 4 g displaying favorable global reactivity parameters. Theoretical IR spectra showed good agreement with experimental results, validating the computational approach. SwissADME predictions indicated favorable pharmacokinetic properties, supporting the drug-likeness of the active compound. The combined experimental, docking, and computational findings highlight compound 4g, along with 4d, as promising antifungal leads for further development.