Conformational and thermodynamic analysis of the COXIB scaffold using quantum chemical calculations

Abstract

Selective cyclo-oxygenase-2 inhibitors (COXIBs) are prominent members of the nonsteroidal anti-inflammatory drugs. The neutral and protonated COXIB scaffold has been subjected to molecular computations in the gas phase and implicit solvent to measure the relative changes in the thermodynamic functions, enthalpy (H rel ), potential energy (U rel ), Gibbs free energy (G rel ) and entropy (S rel ) induced by selected substituents. Conformational analysis of the COXIB scaffold indentified four pairs of atropisomeric conformers (from I, I 0 to IV, IV 0 ) associated with a molecular structure containing a double rotor system. All conformers had similar stability. Para-substitution with substituents that cover a wide range of Hammett sigma values did not alter the geometries of the neutral COXIB conformers; however, the protonated COXIB scaffold was showed an increase in structural and thermodynamic perturbations due to inductive effects. Flexibility and structural resilience of the COXIB scaffold under the conditions studied herein could be an important feature of the COXIBs, especially considering the previously proposed flexibility of the cyclo-oxygenase binding site.