Modification of 4-(4-chlorothiophen-2-yl)thiazol-2-amine derivatives for the treatment of analgesia and inflammation: synthesis and in vitro, in vivo, and in silico studies

Abstract

Inflammation is a protective response to a variety of infectious agents. To develop a new anti-inflammatory drug, we explored a pharmacologically important thiazole scaffold in this study. In a multi-step synthetic approach, we synthesized seven new thiazole derivatives (<b>5a</b>-<b>5g</b>). Initially, we examined the <i>in vitro</i> anti-inflammatory potentials of our compounds using COX-1, COX-2, and 5-LOX enzyme assays. After <i>in vitro</i> confirmation, the potential compounds were subjected to <i>in vivo</i> analgesic and anti-inflammatory studies. The hot plate method was used for analgesia, and carrageenan-induced inflammation was also assayed. Overall, all our compounds proved to be potent inhibitors of COX-2 compared to celecoxib (IC₅₀ 0.05 μM), exhibiting IC₅₀ values in the range of 0.76-9.01 μM .Compounds <b>5b</b>, <b>5d</b>, and <b>5e</b> were dominant and selective COX-2 inhibitors with the lowest IC₅₀ values and selectivity index (SI) values of 42, 112, and 124, respectively. Similarly, in the COX-1 assay, our compounds were relatively less potent but still encouraging. Standard aspirin exhibited an IC₅₀ value of 15.32 μM. In the 5-LOX results, once again, compounds <b>5d</b> and <b>5e</b> were dominant with IC₅₀ values of 23.08 and 38.46 μM, respectively. Standard zileuton exhibited an IC₅₀ value of 11.00 μM. Based on the COX/LOX and SI potencies, the compounds <b>5d</b> and <b>5e</b> were subjected to <i>in vivo</i> analgesic and anti-inflammatory studies. Compounds <b>5d</b> and <b>5e</b> at concentrations of 5, 10, and 20 mg/kg body weight were significant in animal models. Furthermore, we explored the potential role of compounds <b>5d</b> and <b>5e</b> in various phlogistic agents. Similarly, both compounds <b>5d</b> and <b>5e</b> were also significantly potent in the anti-nociceptive assay. The molecular docking interactions of these two compounds with the target proteins of COX and LOX further strengthened their potential for use in COX/LOX pathway inhibitions.