Design, syntheses, and evaluation of 2,3‐diphenylcycloprop‐2‐en‐1‐ones and oxime derivatives as potential cyclooxygenase‐2 (COX‐2) inhibitors with analgesic‐antiinflammatory activity

Abstract

AbstractA group of 2,3‐diphenylcycloprop‐2‐enes having a variety of substituents at the para‐position of the C‐2 phenyl ring (H, F), and C‐3 phenyl ring (H, F, SMe, SOMe, SO2Me), in conjunction with either a C‐1 carbonyl, oxime, oxime acetate, benzoyl hydrazone, or hydrogen substituent were synthesized for in vivo evaluation as analgesic and antiinflammatory (AI) agents, and as potential selective cyclooxygenase‐2 (COX‐2) inhibitors. This group of cycloprop‐2‐ene compounds exhibited significant analgesic activity, since 4% NaCl‐induced abdominal constriction was reduced by 43–90% at 30 min, and 41–100% at 60 min, after drug administration relative to the reference drugs aspirin and celecoxib (58% and 32% inhibition at 30 min after drug administration) for a 50 mg/kg intraperitoneal dose. AI activities, determined using the carrageenan‐induced rat paw edema assay, showed that this class of cycloprop‐2‐ene compounds exhibited AI activities in the inactive‐to‐modest activity range (0–26% inhibition) for a 50 mg/kg oral dose. The AI potency order for a group of 2,3‐diphenylcycloprop‐2‐enes with respect to the C‐1 substituent was oxime>hydrogen>carbonyl>benzoyl hydrazone. 2,3‐Diphenylcycloprop‐2‐en‐1‐one oxime (20) was the most active AI agent, inducing a 26% reduction in inflammation, relative to the reference drugs ibuprofen and celecoxib, which showed 52% and 58% reductions in inflammation, at 5 h after drug administration. In vitro COX‐1 and COX‐2 inhibition studies showed that 2,3‐diphenylcycloprop‐2‐en‐1‐one oxime (20) is a selective COX‐2 inhibitor (COX‐1 IC50>100 μM; COX‐2 IC50=2.94 μM; COX‐2 selectivity index>34). A molecular modeling study that docked the oxime (20) in the active site of the human COX‐2 isozyme showed that it binds in the vicinity of the mouth of the COX‐2 binding site with the O‐atom of the oxime (=N–OH) moiety separated from the NH2 group of Arg120 by about 3.65 Å. This orientation of the oxime compound (20) in the COX‐2 binding site could be due to a potentially strong ionic interaction between the =NOH oxime moiety and the guanidinium moiety of Arg120. Drug Dev. Res. 57:6–17, 2002. © 2002 Wiley‐Liss, Inc.