Design and Synthesis of Some 5-Substituted-2-(4-(azido or methylsulfonyl) phenyl)-1H-indole Derivatives as Selective Cyclooxygenase (COX-2) Inhibitors

Afshin Zarghi

doi:10.3797/scipharm.0805-20

Abstract

A group of 5-substituted-2-(4-azido or (methylsulfonyl)phenyl)-1H-indoles were designed and synthesized as selective cyclooxygenase (COX-2) inhibitors. In vitro COX-1 and COX-2 isozyme inhibition studies were carried out to investigate the effect of different substituents (H, F, Cl, Me, OMe) at C-5 position and different pharmacophore groups (azido or methylsulfonyl) at para position of phenyl ring at C-2 position of the 1H-indole ring on COX-2 selectivity and potency. The structure-activity relationship study of these compounds indicated that the introduction of a methoxy substituent at C-5 position and 4-(methylsulfonyl) phenyl group at C-2 position of the 1H-indole ring (compound 4e) had the best COX-2 selectivity (S.I= 291.2). A molecular modeling study where 4e was docked in the binding site of COX-2 showed that the methylsulfonyl group at para position of phenyl ring is oriented in the vicinity of the COX-2 secondary pocket.

Highlights

Cyclooxygenase (COX) know as prostaglandin synthase (PGH) is a potent mediator of inflammation
The COX-2 isozyme is induced by mitogenic and proinflammatory stimuli linking its involvement to inflammatory processes [3].selective inhibition of COX-2 over COX-1 is useful for the treatment of inflammation and inflammation-associated disorders with reduced gastrointestinal toxicities when compared with Nonsteroidal anti-inflammatory drugs (NSAIDs)
As part of our ongoing program to design new types of selective COX-2 inhibitors, we report the synthesis, some structure-activity relationships, and a molecular modeling study for a group of 2-phenyl-1H-indoles possessing a COX-2 azido or SO2Me pharmacophore at the para-position of phenyl ring in conjunction with an 1H-indole ring having different substituents at C-5 position

Summary

Introduction

Cyclooxygenase (COX) know as prostaglandin synthase (PGH) is a potent mediator of inflammation. Diarylheterocycles, and other central ring pharmacophore templates, have been extensively studied as selective COX-2 inhibitors. All these molecules possess 1,2 diaryl substitution on a central heterocyclic or carbocyclic ring system (see structures A–F in Chart 1) [7,8,9,10,11,12,13]. As part of our ongoing program to design new types of selective COX-2 inhibitors, we report the synthesis, some structure-activity relationships, and a molecular modeling study for a group of 2-phenyl-1H-indoles possessing a COX-2 azido or SO2Me pharmacophore at the para-position of phenyl ring in conjunction with an 1H-indole ring having different substituents at C-5 position

Chemistry

Enzyme Inhibitory Activity

Docking study