A New Class of Acyclic 2-Alkyl-1,1,2-Triaryl (Z)-Olefins as Selective Cyclooxygenase-2 Inhibitors

Abstract

A new class of acyclic (Z)-2-alkyl-1,2-diphenyl-1-(4-methanesulfonylphenyl)ethenes (7) was designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 isozyme inhibition structure-activity studies identified (Z)-1,2-diphenyl-1-(4-methanesulfonylphenyl)oct-1-ene (7d) as a potent COX-2 inhibitor (IC(50) = 0.42 microM) with a high COX-2 selectivity index (SI > 234). In a carrageenan-induced rat paw edema assay, (Z)-7d exhibited excellent antiinflammatory activity (ID(50) = 1.1 mg/kg). The molecular modeling and structure-activity data acquired indicate that (Z)-olefins having cis C-1 4-methanesulfonylphenyl and C-2 unsubstituted phenyl (or 4-acetoxyphenyl) substituents in conjunction with a C-1 phenyl ring and a C-2 alkyl substituent of appropriate length constitute a suitable template for the design of a novel class of acyclic (Z)-2-alkyl-1,1,2-triaryleth-1-ene COX-2 inhibitors.

Design and Synthesis of Benzimidazole Analogs Endowed with Oxadiazole as Selective COX‐2 Inhibitor

“…Synthesized compounds (5a-r) were subjected to inhibit ovine COX-1 and human recombinant COX-2 using an enzyme immunoassay (EIA) kit as described previously [30]. Cyclooxygenase catalyzes the first step in the biosynthesis of arachidonic acid (AA) to PGH 2 .…”

Rofecoxib Analogues Possessing a Nitric Oxide Donor Sulfohydroxamic Acid (SO2NHOH) Cyclooxygenase‐2 Pharmacophore: Synthesis, Molecular Modeling, and Biological Evaluation as Anti‐inflammatory Agents

“…560131, Cayman Chemical, Ann Arbor, MI, USA) according to a previously reported method. [16] Anti-inflammatory assay: In vivo anti-inflammatory activity was measured using a carrageenan-induced rat paw edema assay described by Winter et al [17] In brief, three male Sprague-Dawley rats weighing 160-180 g were used in each group. Test compounds 16-19 suspended in water containing 1 % methyl cellulose were administered orally for a minimum of three different doses (10-50 mg kg À1 ) 1 h prior to a 0.05 mL subcutaneous injection of 1 % carrageenan in 0.9 % NaCl solution under the planter skin of the right hind paw.…”

“…[8] Accordingly, replacement of the methanesulfonylphenyl substituent in rofecoxib (2) with a para-benzenesulfohydroxamic acid moiety offers an attractive drug design concept to circumvent the adverse cardiovascular events associated with the chronic clinical use of highly selective COX-2 inhibitors, particularly rofecoxib. Herein we describe an investigation directed toward the synthesis, molecular modeling, and biological evaluation of NO donor sulfohydroxamic analogues of rofecoxib (compounds [16][17][18][19] that, unlike rofecoxib, may be devoid of adverse cardiovascular effects.…”

“…Chorosulfonation occurred primarily at Figure 1. Some selective COX-2 inhibitors (1 a, 1 c (SC-558), [9] 2, and 3 a), sulfohydroxamic acid analogue of celecoxib (1 b), sulfohydroxamic acid metabolite of valdecoxib (3 b), and the target sulfohydroxamic acid nitric oxide donor analogues of rofecoxib (16)(17)(18)(19).…”

Biological Evaluation and Molecular Docking Study of 3-(4-Sulfamoylphenyl)-4-phenyl-1H-pyrrole-2,5-dione as COX-2 Inhibitor

“…The study of the ability of compound 2l to inhibit ovine COX-1 and human recombinant COX-2 activity were carried out using an enzyme immunoassay (EIA) kit (kit catalog number 560101, Cayman Chemical, Ann Arbor, MI, USA). 10 The efficacy of compound 2l was determined as the concentration causing 50% enzyme a These authors contributed equally to this work. Table 1).…”