Design and synthesis of ( Z)-1,2-diphenyl-1-(4-methanesulfonamidophenyl)alk-1-enes and ( Z)-1-(4-azidophenyl)-1,2-diphenylalk-1-enes: novel inhibitors of cyclooxygenase-2 (COX-2) with anti-inflammatory and analgesic activity

Abstract

A group of novel ( Z)-1,2-diphenyl-1-(4-methanesulfonamidophenyl)alk-1-enes was designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1/COX-2 enzyme inhibition studies identified ( Z)-1,2-diphenyl-1-(4-methanesulfonamidophenyl)oct-1-ene ( 8d) as a highly potent (IC 50 = 0.03 μM), and an extremely selective [COX-2 SI (selectivity index) > 3,333], COX-2 inhibitor that showed good anti-inflammatory (AI) activity (ID 50 = 2.8 mg/kg). A molecular modeling (docking) study showed that the p-MeSO 2NH group present in ( Z )- 8d inserts deep inside the 2°-pocket of the COX-2 binding site, it undergoes a hydrophobic interaction with Ala 516 and Gly 519, and one of the O-atoms of the MeSO 2 group participates in a weak hydrogen bonding interaction with the N H 2 of Arg 513 (distance = 3.85 Å). Similar in vitro COX-1/COX-2 enzyme inhibition studies showed that the azido compound 1-(4-azidophenyl)-1,2-diphenyloct-1-ene ( 9c) is also a potent and selective COX-2 inhibitor (COX-2 IC 50 = 0.11 μM: SI > 909) that exhibits good AI activity (ID 50 = 5.0 mg/kg). A docking experiment to determine the orientation of ( Z )- 9c within the COX-2 binding site showed that the linear p-N 3 group inserts into the COX-2 2°-pocket, where it undergoes an ion–ion (electrostatic) interaction with Arg 513. Structure–activity data acquired indicate that an olefin having either a C-1 p-MeSO 2NH–phenyl, or a p-N 3–phenyl, substituent, that is, cis to a C-2 unsubstituted phenyl substituent, in conjunction with C-1 unsubstituted phenyl and C-2 alkyl substituents, provides a novel template to design acyclic olefinic COX-2 inhibitors.