Synthesis and cyclooxygenase inhibition of various (aryl-1,2,3-triazole-1-yl)-methanesulfonylphenyl derivatives

A series of 1,4- and 1,5-diaryl substituted 1,2,3-triazoles was synthesized by either Cu( I)-catalyzed or Ru( II)-catalyzed 1,3-dipolar cycloaddition reactions between 1-azido-4-methane-sulfonylbenzene 9 and a panel of various para-substituted phenyl acetylenes ( 4- H, 4- Me, 4- OMe, 4- NMe2, 4- Cl, 4- F). All compounds were used in in vitro cyclooxygenase ( COX) assays to determine the combined electronic and steric effects upon COX-1 and COX-2 inhibitory potency and selectivity. Structure-activity relationship studies showed that compounds having a vicinal diaryl substitution pattern showed more potent COX-2 inhibition (IC50 = 0.03-0.36 mu M) compared to their corresponding 1,3-diaryl-substituted counterparts (IC50 = 0.15 to > 10.0 mu M). In both series, compounds possessing an electron-withdrawing group ( Cl and F) at the para-position of one of the aryl rings displayed higher COX-2 inhibition potency and selectivity as determined for compounds containing electron-donating groups ( Me, OMe, NMe2). The obtained data show, that the central carbocyclic or heterocyclic ring system as found in many COX-2 inhibitors can be replaced by a central 1,2,3-triazole unit without losing COX-2 inhibition potency and selectivity. The high COX-2 inhibition potency of some 1,2,3-triazoles having a vicinal diaryl substitution pattern along with their ease in synthesis through versatile Ru( II)-catalyzed click chemistry make this class of compounds interesting candidates for further design and synthesis of highly selective and potent COX-2 inhibitors. (c) 2009 Elsevier Ltd. All rights reserved.