New pyrimidine/thiazole hybrids endowed with analgesic, anti-inflammatory, and lower cardiotoxic activities: Design, synthesis, and COX-2/sEH dual inhibition.

ABSTRACT

Some cyclooxygenase (COX)-2 selective medications were withdrawn from the market just a few years after their production due to cardiovascular side effects. In this study, a new series of pyrimidine/thiazole hybrids 7a-p was synthesized as selective COX-2/soluble epoxide hydrolase (sEH) inhibitors with analgesic and anti-inflammatory effects, and lower cardiotoxicity effects. The target compounds were synthesized and in vitro tested against COX-1, COX-2, and sEH enzymes. Hybrids 7j, 7k, and 7i showed the greatest COX-2-inhibitory activity and were discovered to be the most potent dual COX-2/sEH inhibitors. In vivo tests revealed that these hybrids were the most active analgesic/anti-inflammatory agents, with improved ulcerogenic and cardioprotective properties. Finally, the most active dual inhibitors were docked into COX-2/sEH active regions to explain their binding mechanisms.