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 µM) and 5-LOX (IC50 = 0.46 ± 0.02 µM) with comparable efficacy to celecoxib (IC50 = 0.08 ± 0.0004 µM) and surpassing the standard Zileuton (IC50 = 0.69 ± 0.03 µM). Additionally, compound 4c had the highest potency as a soluble epoxide hydrolase (sEH) inhibitor, with an IC50 of 4.30 ± 0.19 µM, 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. Their 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.