New Diaryl-1,2,4-triazolo[3,4-]pyrimidine Hybrids as Selective COX-2/sEH Dual Inhibitors with Potent Analgesic/Anti-inflammatory and Cardioprotective Properties.

COX-2-selective drugs were withdrawn from the market just a few years after their development due to cardiovascular side effects. As a result, developing a selective COX-2 inhibitor as an anti-inflammatory agent with cardioprotective characteristics has become a prominent objective in medicinal chemistry. New 15 diaryl-1,2,4-triazolo[3,4-]pyrimidine hybrids - were synthesized and investigated as dual COX-2/sEH inhibitors. Compounds , , and have the highest potency and selectivity as COX-2 inhibitors (IC = 15.20, 11.60, and 10.50 μM, respectively; selectivity index (COX-1/COX-2) = 13, 20, and 25, respectively), compared to celecoxib (COX-2; IC = 42 μM; SI = 8). The 5-LOX inhibitory activity of compounds , , and was further examined . Compounds and , the most effective COX-2 selective inhibitors, demonstrated stronger 5-LOX inhibitory action than the reference quercetin, with IC values of 2.90 and 3.05 μM, respectively. Additionally, compounds , , and were the most potent dual COX-2/sEH inhibitors, with IC values against sEH of 3.20, 2.95, and 2.20 nM, respectively, and were equivalent to AUDA (IC = 1.2 nM). investigations also demonstrated that these compounds were the most efficacious as analgesic/anti-inflammatory derivatives with a high cardioprotective profile against cardiac biomarkers and inflammatory cytokines. The docking data analysis inquiry helped better understand the binding mechanisms of the most active hybrids within the COX-2 active site and supported their COX-2 selectivity. Compounds , , and exhibited a similar orientation to rofecoxib and celecoxib, with a larger proclivity to enter the selectivity side pocket than the reference compounds.