Design, synthesis, and biological evaluation of novel pyrimidine–sulfonamide derivatives as multi-targeted COX-2/5-LOX/sEH inhibitors with potential antiproliferative properties

Cyclooxygenase-2 (COX-2) and lipoxygenases (LOXs), two enzymes involved in arachidonic acid metabolism, have been linked to various cancers. As a result, it was exciting to develop dual COX-2/5- LOX inhibitors for promoting the development of new treatments. This study examines the synthesis and in vitro pharmacological properties of pyrimidine–sulfonamide derivatives. Compounds 4c, 4g, 4j, 4m, and 4o were the most effective COX-2 inhibitors and showed substantial inhibitory activity against 5-LOX. Compound 4c demonstrated significant inhibition of COX-2 (IC50 = 0.11 ± 0.01 mM) and 5-LOX (IC50 = 0.46 ± 0.02 mM) with comparable efficacy to celecoxib (IC50 = 0.08 ± 0.0004 mM) and surpassing the standard Zileuton (IC50 = 0.69 ± 0.03 mM). Additionally, compound 4c had the highest potency as a soluble epoxide hydrolase (sEH) inhibitor, with an IC 50 of 4.30 ± 0.19 mM, demonstrating 1.6-fold lower potency than the reference AUDA but 5-fold greater potency than celecoxib. Compounds 4c, 4g, and 4j showed promising antiproliferative activity, with compound 4c being the most potent against the pancreatic (Panc-1) cancer cell line, and compound 4j the most effective against the breast MCF-7 cancer cell line. ... mehrTheir efficacy against these two cell lines exceeded that of the reference compounds celecoxib, sorafenib, and doxorubicin. Docking analysis of compound 4c showed a good fit within the active sites of both COX-2 and human sEH.