Harnessing thiazole chemistry for antifungal strategies through an experimental and computational chemistry approach: anti-biofilm, molecular docking, dynamics, and DFT analysis.

This study reports the design, synthesis, and evaluation of four novel ()-2-(2-(1-(5-chlorothiophen-2-yl)ethylidene)hydrazineyl)-4-(aryl)thiazole derivatives (4a-4d) as potential anti-biofilm agents against . The compounds were structurally characterized by FT-IR, H NMR, C NMR, and HRMS spectral techniques. Biofilm inhibition assays revealed that derivatives 4a-4c suppressed over 50% of biofilm formation at a concentration of 12.5 μg mL, although exopolysaccharide production remained largely unaffected. Molecular docking indicated strong binding affinities toward lanosterol 14α-demethylase, with 4a achieving the highest docking score (-8.715 kcal mol) through hydrogen bonding and π-π stacking interactions. Stability of the 4c-protein complex was confirmed by molecular dynamics simulations, supported by RMSD and flexibility analyses. An in-depth computational analysis was also performed on the most active thiazole derivative, compound 4c. DFT and NBO analyses of 4c indicated favourable geometry and key electron delocalization, while ELF, LOL, NCI, and RDG studies highlighted the role of non-covalent interactions in stabilizing the molecular framework. Additionally, the ADME profile of 4c demonstrated favourable pharmacokinetic properties, including high gastrointestinal absorption and a moderate lipophilicity index, highlighting its potential as a lead antifungal scaffold.