Structural Properties and Anti-Inflammatory Activity of Acetamide Thiazole Derivatives: Density Functional Theory and Schrödinger Suites

Abstract

Acetamide thiazole derivatives have been synthesized by refluxing 4-(4-chlorophenyl)thiazol-2-amine with 2-phenoxyacetic acid by using 2,6-lutidine as a base and o-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyl uranium tetra fluoro borate as coupling agent in dichloromethane solvent. The final compounds were confirmed by single crystal X-ray diffraction technique. Density functional theory (DFT) with B3LYP/6-311++G(d,p) functional and basis set have been applied to investigate the nucleophiles/electrophiles sites as well as highest occupied and lowest unoccupied molecular orbitals (HOMO-LUMO) with relative chemical reactivity parameters. The derivatives have been evaluated for the anti-inflammation activity against Cyclooxygenase protein receptors (COX-1 and COX-2), where inhibition of COX represents a prospective drug marker for inflammation. In silico molecular docking simulations were subjected for these molecules against COX-1 and COX-2 protein receptors using Schrödinger suite via Glide 5.5 module (Grid-based ligand docking with energetics) that revealed prominent interactions of ligands with receptor at active sites via strong hydrogen bonds, pi-cation and pi-pi stacking interactions with ARG120 and TYR355 amino acids. And furthermore, the stability of the protein-ligand conformations has been investigated by molecular dynamics studies via Desmond module that ensured the compactness and higher plausibility of the predicted models. In vitro assay against cyclooxygenase enzymes (COX-1 and COX-2) gave IC50 values of the molecules, which showed better inhibitor for COX-1 and COX-2 targets. Structure-based correlation analysis was made on the results obtained from DFT and Schrödinger suites. The present study outcomes suggested that the molecules under study were proven to be prospective drug candidates.