Synthesis of celecoxib analogs that possess a N-hydroxypyrid-2(1H)one 5-lipoxygenase pharmacophore: Biological evaluation as dual inhibitors of cyclooxygenases and 5-lipoxygenase with anti-inflammatory activity

A hitherto unknown class of celecoxib analogs was designed for evaluation as dual inhibitors of the 5-lipoxygenase/cyclooxygenase-2 (5-LOX/COX-2) enzymes. These compounds possess a SO(2)Me (11a), or SO(2)NH(2) (11b) COX-2 pharmacophore at the para-position of the N(1)-phenyl ring in conjunction with a 5-LOX N-hydroxypyrid-2(1H)one iron-chelating moiety in place of the celecoxib C-5 tolyl group. The title compounds 11a-b are weak inhibitors of the COX-1 and COX-2 isozymes (IC(50) = 7.5-13.2 mu M range). In contrast, the SO(2)Me (11a, IC(50) = 0.35 mu M), and SO(2)NH(2) (11b, IC(50) = 4.9 mu M), compounds are potent inhibitors of the 5-LOX enzyme comparing favorably with the reference drug caffeic acid (5-LOX IC(50) = 3.47 mu M). The SO(2)Me (11a, ED(50) = 66.9 mg/kg po), and SO(2)NH(2) (11b, ED(50) = 99.8 mg/kg po) compounds exhibited excellent oral anti-inflammatory (AI) activities being more potent than the non-selective COX-1/COX-2 inhibitor drug aspirin (ED(50) = 128.9 mg/kg po) and less potent than the selective COX-2 inhibitor celecoxib (ED(50) = 10.8 mg/kg po). The N-hydroxypyridin-2(1H) one moiety constitutes a novel pharmacophore for the design of cyclic hydroxamic mimetics capable of chelating 5-LOX iron for exploitation in the design of 5-LOX inhibitory AI drugs. (C) 2008 Elsevier Ltd. All rights reserved.