Synthesis and biological evaluation of linear phenylethynylbenzenesulfonamide regioisomers as cyclooxygenase-1/-2 (COX-1/-2) inhibitors

Abstract

A group of regioisomeric phenylethynylbenzenesulfonamides possessing a COX-2 SO 2NH 2 pharmacophore at the para-, meta- or ortho-position of the C-1 phenyl ring, in conjunction with a C-2 substituted-phenyl (H, OMe, OH, Me, F) group, were synthesized and evaluated as inhibitors of the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isozymes. The target 1,2-diphenylacetylenes were synthesized via a palladium-catalyzed Sonogashira cross-coupling reaction. In vitro COX-1/-2 isozyme inhibition structure–activity data showed that COX-1/-2 inhibition and the COX selectivity index (SI) are sensitive to the regioisomeric placement of the COX-2 SO 2NH 2 pharmacophore where the COX-2 potency order for the benzenesulfonamide regioisomers was generally meta > para and ortho. Among this group of compounds, the in vitro COX-1/-2 isozyme inhibition studies identified 3-(2-phenylethynyl)benzenesulfonamide ( 10a) as a COX-2 inhibitor (COX-2 IC 50 = 0.45 μM) with a good COX-2 selectivity (COX-2 SI = 70). In contrast, 2-[2-(3-fluorophenyl)ethynyl]benzenesulfonamide ( 11c) possessing a SO 2NH 2 COX-2 pharmacophore at the ortho-position of the C-1 phenyl ring exhibited COX-1 inhibition and selectivity (COX-1 IC 50 = 3.6 μM). A molecular modeling study where 10a was docked in the binding site of COX-2 shows that the meta-SO 2NH 2 COX-2 pharmacophore was inserted inside the COX-2 secondary pocket (Arg513, Phe518, Val523, and His90). Similar docking of 10a within the COX-1 binding site shows that the meta-SO 2NH 2 pharmacophore is unable to interact with the respective amino acid residues in COX-1 that correspond to those near the secondary pocket in COX-2 due to the presence of the larger Ile523 in COX-1 that replaces Val523 in COX-2.