QSAR analysis of centrally fused 1,5-diaryl pyrazoles for cyclooxygenase inhibition using MOE-Qua-SAR descriptors

Abstract

Quantitative structure–activity relationship (QSAR) analysis has been carried out on a series of conformationally restricted 1,5-diaryl pyrazoles reported as selective cyclooxygenase-2 (COX-2) inhibitors in order to explore the selectivity requirements for COX-2 inhibition among these congeners. QSAR analysis was based on regression analysis between various computed physicochemical and topological descriptors and biological activity. Derived QSAR models evinced a satisfactory correlation of COX-2 inhibitory potency with a three-dimensional (3D) spatial descriptor, std_dim3, and a two-dimensional (2D) partial charge descriptor, PEOE_VSA-1. Balaban J, a highly discriminating topological descriptor, was found to play an imperative role in governing both COX-1 inhibitory potency as well as selective inhibition of COX-2 over COX-1. The selective COX-2 inhibition could be influenced by the size, shape, and polarizability of the whole molecules and was discerned by the contribution of molar refractivity (MR), Balaban J descriptors. The findings are in good consonance with earlier X-ray crystallographic investigations of binding mode of these types of selective COX-2 inhibitors. Results discussed herein bring important structural insights to aid the design and development of novel COX-2 inhibitors.