Structural Modification of Aceclofenac to Design Enhanced COX-2 Inhibitors: A Medicinal and Toxicological Study

Aceclofenac (ACF) is a nonsteroidal anti-inflammatory drug (NSAID), prescribed for treating pain and inflammation. It prevents the synthesis of prostaglandin E2 by inhibiting the activity of cyclooxygenases (COX). Upon its oral administration, evidence of gastric ulcers, hypersensitivity reactions, vasculitis, nephritis, premature fetal deliveries, etc., has been reported. So, scientists feel the necessity to look for alternatives with enhanced activity along with minimized side effects. Structural modification serves as a gold standard for such discovery. We aimed to develop a superior alternative to ACF with minimal adverse effects. We altered the fundamental structure of ACF by incorporating various functional groups. Density functional theory (DFT) was implemented with the B3LYP/6-31g ([Formula: see text], [Formula: see text] basis set for geometrical optimization of the structures. Thermodynamics, molecular orbitals, electrostatic potentials, and vibrational frequencies of the structures were analyzed. We conducted molecular docking and molecular dynamics simulation (MD) studies of the derivatives on the prostaglandin synthase protein (COX-2). PASS and ADMET were investigated in order to forecast their pharmacological properties. Our derivatives exhibited improved physicochemical properties and binding affinity. For their optimal performances, ACF19, ACF10, ACF14, and ACF23 were selected, each with a docking score of −8.3 kcal/mol, −8.1 kcal/mol, −8.1 kcal/mol, and −8.1 kcal/mol, respectively. MD simulation further confirmed the stable tendencies of the selected derivative complexes. The derivatives showed decreased toxicity and enhanced pharmacological properties. Therefore, the study has identified potentially safer drug candidates that could serve as alternatives to ACF.