Structural tailoring of etoricoxib: A spectrochemical, medicinal and pharmacological study

Etoricoxib (ETC), a selective cyclooxygenase enzyme (COX-2) inhibitor, is widely utilized to manage pain and inflammation. Nevertheless, its therapeutic efficacy is limited by poor aqueous solubility, low bioavailability, and significant cardiovascular risks, including increased blood pressure, thrombosis, and the potential for myocardial infarction. This study aimed to address these limitations through structural modifications of etoricoxib. A total of 21 derivatives were designed by introducing various functioning sets at the R3, R2, and R1 sites of ETC. Quantum chemical calculations were performed to assess alterations in physicochemical properties, such as HOMO–LUMO energy gaps, electrostatic potential, enthalpy, and dipole moments. Notably, most of the derivatives showed improved binding affinities, particularly ETC9 and ETC19, demonstrating the highest binding interactions in molecular docking studies (-10.1 and -10.8 kcal/mol, respectively). Furthermore, molecular dynamics (MD) simulations accomplished by exploiting the YASARA dynamics software program with the AMBER14 energy field throughout 100 ns revealed that the ETC9 and ETC19 derivatives exhibited enhanced stability and flexibility profiles compared to the parent drug, ETC. ADMET and PASS predictions confirmed the drug-like properties of most derivatives, particularly ETC19 and ETC9, which also showed improved absorption, better blood-brain barrier penetration, and reduced toxicity. These outcomes underscore the prospect of the de novo-designed etoricoxib analogues as safer and more effective alternatives, effectively addressing the pharmacological limitations and safety concerns associated with the parent drug.