Synthesis and prostaglandin synthase inhibitory activity of new aromatic O-alkyloxime ethers substituted with methylsulfonamido or methylsulfonyl groups on their aliphatic portion.
Some aromatic O-alkyloxime ethers substituted with methylsulfonamido (7) or methylsulfonyl (8) groups on their aliphatic portions were prepared as analogues of structurally related cyclooxygenase (COX) inhibitors (6) bearing a carboxylic group typical of the classic non-steroidal anti-inflammatory drugs (NSAIDs) in the place of the sulfurated moiety. In addition, also analogues of compounds 8 in which the aliphatic chain is further lengthened by 1 (9), 2 (10), or 3 (11) carbon atoms were synthesized. All compounds (7-11) were tested in vitro towards COX2, and compounds 7-9 towards COX1, by measuring prostaglandin E2 (PGE(2)) production in activated J774.2 macrophages and U937 cell lines, respectively. While all new compounds were found to possess little or no activity on the COX2 isoenzyme, some of these (7a-7d, 8a, 8d, 9e and 9f) appeared to possess an appreciable activity on COX1, with % inhibition values at a concentration of 1 microM ranging from 30% of 8a to 76% of 9e. The COX1 selectivity of the new compounds was tentatively explained by means of a docking study of one of the more active compounds tested on both COX isoenzymes (7d), which indicated a different number of hydrogen bonding interactions with the Arg120 of the active sites of the two enzymes, and therefore, an energetically favored interaction (3.5 kcal/mol) with COX1, compared with COX2.
D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004987:Ethers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005227:Fatty Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D008565:Membrane Proteins; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020298:U937 Cells
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004987:Ethers; D005227:Fatty Acids; D007527:Isoenzymes; D008565:Membrane Proteins; D010091:Oximes; D013449:Sulfonamides; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases