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

A group of 2,3-diphenylcycloprop-2-enes having a variety of substituents at the paraposition of the C-2 phenyl ring (H, F), and C-3 phenyl ring (H, F, SMe, SOMe, SO 2 Me), 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 oxime4hydrogen4carbonyl4benzoyl 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 IC 50 4100 mM; COX-2 IC 50 ¼ 2.94 mM; COX-2 selectivity index434). 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 NH 2 group of Arg 120 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 Arg 120 . Drug Dev.

Stereo- and Regioselective 1,3-Dipolar Cycloaddition of the Stable Ninhydrin-Derived Azomethine Ylide to Cyclopropenes: Trapping of Unstable Cyclopropene Dipolarophiles

“…Cyclopropenes 1a , 1b , 1c , 1o , 1d , 1e , 1f , 1l , 1m , 1g – j , 1k , 1n , 2a , 2b , 2c , 2d , 2e , 2f , 2g – i , 3b , and 3c were prepared according to the literature data. Parent cyclopropene ( 3a ) was obtained according to a literature procedure with slight modifications .…”

Synthesis of Functionalized 3-Spiro[cyclopropa[a]pyrrolizine]- and 3-Spiro[3-azabicyclo[3.1.0]hexane]oxindoles from Cyclopropenes and Azomethine Ylides via [3 + 2]-Cycloaddition

“…All reagents were used as purchased from commercial suppliers without further purification. Starting materials that were not commercially available were synthesized by the previously reported methods. , All solvents were dried by standard procedures and freshly distilled prior to use. The progress of reactions was monitored by TLC on Silufol UV-254 plates using UV light and iodine for detection.…”

Current Status of COX-2 Inhibitors

“…Based upon this hypothesis, compounds with vicinal diaryl rings on cycloprop-2-en-1-one have been investigated as COX-2 inhibitors. In-vitro COX-1 and COX-2 inhibition studies showed that 2,3-diphenylcycloprop-2-en-1-one oxime 105 (Chart 35) is a selective COX-2 inhibitor [95]. Among a group of (Z)-and (E)-1,1-dihalo-2-(4-substituted-phenyl)-3-phenylcyclopropanes evaluated for analgesic and anti-inflammatory properties, compound 106 (Chart 35) with E-configuration inhibited COX-1 (IC 50 = 278.8 M) and COX-2 (IC 50 = 80.5 M) for a COX-2 selectivity index of 3.5 [96].…”