Synthesis and biological evaluation of salicylic acid and N-acetyl-2-carboxybenzenesulfonamide regioisomers possessing a N-difluoromethyl-1,2-dihydropyrid-2-one pharmacophore: dual inhibitors of cyclooxygenases and 5-lipoxygenase with anti-inflammatory activity.
A novel class of salicylic acid and N-acetyl-2-carboxybenzenesulfonamide regioisomers possessing a N-difluoromethyl-1,2-dihydropyrid-2-one pharmacophore attached to its C-4 or C-5 position was designed for evaluation as anti-inflammatory (AI) agents. Replacement of the 2,4-difluorophenyl ring in diflunisal by the N-difluoromethyl-1,2-dihydropyrid-2-one moiety provided compounds showing dual selective cyclooxygenase-2 (COX-2)/5-lipoxygenase (5-LOX) inhibitory activities. AI structure-activity studies showed that the C-4 (14a) and C-5 (14b) salicylate regioisomers were 1.4- and 1.6-fold more potent than aspirin, and the C-5 N-acetyl-2-carboxybenzenesulfonamide regioisomer (22b) was 1.3- and 2.8-fold more potent than ibuprofen and aspirin, respectively. In vivo ulcer index (UI) studies showed that the 4- and 5-(N-difluoromethyl-1,2-dihydropyrid-2-one-4-yl)salicylic acids (14a and 14b) were completely non-ulcerogenic since no gastric lesions were present (UI=0) relative to aspirin (UI=57) at an equivalent mumol/kg oral dose. The N-difluoromethyl-1,2-dihydropyridin-2-one moiety provides a novel 5-LOX pharmacophore for the design of cyclic hydroxamic mimetics for exploitation in the development of dual COX-2/5-LOX inhibitory AI drugs.
Chowdhury
Morshed A
MA
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alta, Canada T6G 2N8.
Abdellatif
Khaled R A
KR
Dong
Ying
Y
Das
Dipankar
D
Yu
Gang
G
Velázquez
Carlos A
CA
Suresh
Mavanur R
MR
Knaus
Edward E
EE
D001241:Aspirin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007536:Isomerism; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012459:Salicylates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000096926:Benzenesulfonamides
D001241:Aspirin; D052246:Cyclooxygenase 2 Inhibitors; D016859:Lipoxygenase Inhibitors; D011728:Pyridones; D012459:Salicylates; D013449:Sulfonamides; C539871:2-(N-difluoromethyl-1,2-dihydropyridin-2-one); C503937:N-acetyl-2-carboxymethylbenzenesulfonamide; D000096926:Benzenesulfonamides