Design, synthesis and anti-inflammatory/analgesic evaluation of novel di-substituted urea derivatives bearing diaryl-1,2,4-triazole with dual COX-2/sEH inhibitory activities

•Two series of diaryl 1,2,4-triazole linked to amide (5a-e) or urea conjugates (10a-f) were synthesized.•Dual in vitro evaluation of the newly synthesized compounds against COX-2/sEH.•Novel compounds were investigated for in vivo analgesic/anti-inflammatory activities.•In silico ADME physicochemical parameters of the novel compounds were determined.•Compounds 10e and 10c revealed the highest in vitro/in vivo activities. Herein, two novel series of diaryl-1,2,4-triazole hybrid to amide conjugates (5a-e) or urea conjugates (10a-f) have been synthesized followed by in vitro evaluation against cyclooxygenase-2/soluble epoxide hydrolase (COX-2/sEH) enzymes using ELISA enzyme assays. In vivo analgesic and anti-inflammatory activities for the new compounds have been carried out using the reported animal protocols. The preliminary results revealed that compounds 10e and 10c were the most active compounds against both COX-2/sEH enzymes (COX-2 IC50 = 1.98 µM and 2.13 µM; sEH = 1.09 and 1.23 nM, respectively). Moreover, the in vivo screening assays confirmed their superiority compared to the other derivatives by exhibiting higher anti-inflammatory and analgesic activity (91.27 and 89.32% edema inhibition; 55.97–50.00% writhing inhibition, respectively) than celecoxib (88.30% edema inhibition; 13.43% writhing inhibition). Collectively, compounds 10e and 10c can be considered as promising dual COX-2/sEH inhibitors with expected less cardiovascular adverse effects affording good anti-inflammatory and analgesic leads for further optimization. [Display omitted]