Discovery of potential anti-inflammatory drugs: diaryl-1,2,4-triazoles bearing N-hydroxyurea moiety as dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase

摘要

A series of hybrids from diaryl-1,2,4-triazole and hydroxamic acid or N-hydroxyurea were synthesized and evaluated as novel anti-inflammatory agents. The biological data showed that (ⅰ) all the compounds showed dual COX-2/5-LOX inhibitory activities in vitro, and 15e showed optimal inhibitory activities (COX-2: IC_(50) = 0.15 μM. 5-LOX: IC_(50) = 0.85 μM). (ⅱ) 15e selectively inhibited COX-2 relative to COX-1 with selectivity index (SI = 0.012) comparable to celecoxib (SI = 0.015). (ⅲ) 15e exhibited potent anti-inflammatory activity (inhibition: 54.1%) which was comparable to the reference drug celecoxib (inhibition: 46.7%) in a xylene-induced ear edema assay, and (ⅳ) 15e displayed promising analgesic activity in acetic acid-induced writhing response and hot-plate assay. Finally, a molecular modeling study revealed the binding interactions of 15e with COX-2 and 5-LOX. Our findings suggest that 15e may be a promising anti-inflammatory agent for further evaluation.