Quantitative structure–activity relationship analysis of 2,3-diaryl indoles as selective cyclooxygenase-2 inhibitors

Abstract

Quantitative structure–activity relationship (QSAR) studies have been performed on a combined series of 2-sulfonylphenyl-3-phenyl-indoles and 2-phenyl-3-sulfonylphenyl-indoles with a common 2,3 vicinal diaryl indole scaffold, recently reported as selective COX-2 inhibitors. This study is aimed to throw light on this, special class of diaryl heterocyclic family of selective COX-2 inhibitors. A preliminary Fujita-Ban analysis on 32 compounds provided valuable insights about the role of different substituents R1 and R2 around the 2,3 vicinal diaryl rings and R3, at position-5 of the central indole moiety in explaining their in vitro COX-2 inhibitory activity. The contribution of R1, R2, R3 towards COX-2 inhibitory activity resulted in statistically significant linear multiple regression equation with r = 0.942, r2 = 0.888, s = 0.532 and F = 7.92, q2 = 0.516 for 29 compounds. Fujita-Ban model shows a negative contribution of SO2NH2 and SO2CH3 at the R1 position; a negative contribution of 4-Cl, 2-Cl, 3-Cl, 3-CH3, 4-SO2CH3, 4-Br and a positive contribution of 4-OCH3, 4-CH3 substituents at the R2 position. At the R3 position a negative contribution of F, Br and a positive contribution of Cl, CH3 is encountered. In the light of our preliminary investigation that electron donating groups at the para position of R2 are conducive for COX-2 inhibitory activity from the Fujita-Ban model, we attempted to correlate the COX-2 inhibitory activity with quantum chemical descriptors of semi-empirical AM1 optimized geometries of the title compounds. Correlation analysis showed the molecular electronic descriptor, MOPAC total energy as crucial in governing COX-2 inhibitory activity of all the reported 41 compounds.