Design, syntheses, and evaluation of novel 1,1‐dihalo‐2,3‐diphenylcyclopropanes as potential cyclooxygenase‐2 (COX‐2) inhibitors with analgesic‐antiinflammatory activity

Abstract

A group of (Z)-and (E)-1,1-dihalo-2-(4-substituted-phenyl)-3-phenylcyclopropane [(Z)-10, (E)-11] stereoisomers having a variety of substituents (H, Br, Cl, F, NO 2 , SO 2 Me) at the para-position of the C-2 phenyl ring in conjunction with either two chloro or bromo substituents at C-1 were synthesized for in vivo evaluation as analgesic and antiinflammatory (AI) agents, and as potential selective cyclooxygenase-2 (COX-2) inhibitors. This group of compounds (10-11) exhibited significant analgesic activity since 4% NaClinduced abdominal constriction was reduced by 44-73% at 30 min, and 48-77% at 60 min, post-drug administration relative to the reference drugs aspirin and celecoxib (58 and 32% inhibition at 30 min postdrug administration) for a 50 mg/kg intraperitoneal dose. In the 1,1-dichloro group of compounds, a Cl or MeSO 2 substituent at the para-position of the C-2 phenyl ring generally provided superior analgesic activity. The most active analgesic compound, (E)-1,1-dichloro-2-(4-methanesufonylphenyl)-3-phenylcyclopropane (11h) inhibited abdominal constriction by 72 and 77% at 30 and 60 min post-drug administration, respectively. AI activities, determined using the carrageenan-induced rat paw edema assay, showed that this class of (Z)-10 and (E)-11 compounds exhibited AI activities in the inactive-to-moderate activity range (1.5-45% inhibition) for a 50 mg/kg oral dose. The AI potency order, with respect to the para-substitutent on the C-2 phenyl ring, for the (Z)-10 compounds was NO 2 > MeSO 2 ≈ H ≥ Cl, and for the (E)-11 compounds was H ≥ MeSO 2 > Cl ≈ Br. (E)-1,1-dibromo-2-(4-methanesufonylphenyl)-3-phenylcyclopropane (11l), which was the most active AI compound, reduced inflammation by 45 and 37% at 3 and 5 h post-drug administration, respectively. The (E)-11 stereoisomer was generally a more potent AI agent than the corresponding (Z)-10 stereoisomer. In vitro COX-1 and COX-2 inhibition studies showed that (E)-1,1-dichloro-2-(4-nitrophenyl)-3-phenylcyclopropane (11c) inhibited COX-1 (IC 50 = 278.8 µM) and COX-2 (IC 50 = 80.5 µM) for a COX-2 selectivity index of 3.5, whereas (E)-1,1-dichloro-2-(4-methanesulfonylphenyl)-3-phenylcyclopropane (11h) was a more potent inhibitor of COX-1 and COX-2, but it was more selective for COX-1 (COX-1 IC 50 = 0.59 µM, COX-2 IC 50 = 3.04 µM). A molecular modeling (docking) study for (E)-1,1-dichloro-2-(4-methanesulfonylphenyl)-3-phenylcyclopropane (11h) on the active site of the human COX-2 isozyme shows it binds in the center of the active site with the 1,1-dichloro substituents oriented in the direction of the mouth of the channel towards Arg 120, and the C-2 MeSO 2 moiety oriented towards the apex of the active site with the S-atom of the MeSO 2 substituent positioned about 6.56 Å inside the entrance to the secondary pocket (Val 523 ) of COX-2. In contrast, the corresponding (Z)-10h stereoisomer assumes a different position

Current Status of 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].…”