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Some cyclooxygenase (COX)-2 selective medications were withdrawn from the market just a few years after their production due to cardiovascular side effects.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 antiinflammatory 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.

Design and synthesis of new dihydropyrimidine/sulphonamide hybrids as promising anti-inflammatory agents via dual mPGES-1/5-LOX inhibition

“…As part of our ongoing search for a highly safe and effective antiinflammatory drug (Elbastawesy et al, 2015;Abdelrahman et al, 2017;Youssif et al, 2019;Abdel-Aziz et al, 2021;Hendawy et al, 2021;Mohassab et al, 2021;Abdel et al, 2022;Shawky et al, 2023), we aimed to fill the research gap on the limited investigation of dihydropyrimidines' potential as dual mPGES-1 and 5-LOX inhibitors in the current study. Our main objective was to explore the anti-inflammatory properties of novel dihydropyrimidine/ sulfonamide hybrids (3a-j), taking advantage of the known antiinflammatory potencies of both components.…”

Small Molecules as Anti‐inflammatory Agents: Molecular Mechanisms and Heterocycles as Inhibitors of Signaling Pathways

“…In vitro study reveals that 20 a, 20 b, and 20 c showed the greatest analgesic/anti-inflammatory, and better ulcerogenic, cardioprotective properties (Figure 13). [117][118][119] Chen et al studied the design, and synthesis of a series of novel 4-indolyl-2-aminopyrimidine with anti-inflammatory potential. In these analogs, 21 a and 21 b showed strong inhibition for IL-6 and IL-8 with no significant cytotoxicity in vitro.…”

“…In vitro study reveals that 20 a , 20 b , and 20 c showed the greatest analgesic/anti‐inflammatory, and better ulcerogenic, cardioprotective properties (Figure 13). [117–119] …”

A comprehensive review of recent advances in the biological activities of quinazolines

“…Traditional NSAIDs have a multitude of side effects, including gastrointestinal toxicity due to COX-1 inhibition, which is essential for the integrity of the stomach mucosa. COX-2 is an inducible type that is activated when an inflammatory stimulus is present (Abdelazeem et al, 2017;Abdel-Aziz et al, 2022;Abdelrahman & Youssif, 2017;Hendawy et al, 2021;Mohassab et al, 2021;Youssif et al, 2006Youssif et al, , 2019. As a result, the development of new COX-2 selective anti-inflammatory drugs is a hotly disputed research area, Figure 7.…”