Synthesis, hydrolysis, and COX-2/15-LOX inhibitory evaluation of 4-Acetamidophenyl 4-Bromobenzoates

The enzymes cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX) metabolize arachidonic acid and have been associated with the onset and progression of several disorders, including various inflammatory diseases. Dual COX-2/15-LOX inhibition is a useful approach to develop drugs with enhanced biological activities and reduced off-target drug actions, with a wider range of anti-inflammatory properties as compared to traditional NSAIDs. In the current work, we designed and developed a number of arylated carboxylate acetaminophen analogues as COX-2/15-LOX dual inhibitors. Compounds 5b, 5d, and 5e exhibited moderate COX-2 inhibitory activity (IC₅₀ = 1.44 ± 0.10, 1.80 ± 0.14, & 2.39 ± 0.11 µM) in vitro assay. Compound 5c had higher COX-2 selectivity (IC₅₀ = 0.18 ± 0.05 µM) than celecoxib (IC₅₀ = 0.33 ± 011 µM). Compared to the quercetin (standard inhibitor), with an IC₅₀ = 15.8 ± 0.61 µM that all synthesized analogues exhibited significantly improved inhibitory activity towards 15-LOX and compound 5c was found to be the most effective 15-LOX inhibitor (IC₅₀ = 0.14 ± 0.18 µM). Moreover, molecular docking closely aligns with in vitro studies, revealing the specific interactions towards synthesized derivatives (5a–5f) and target proteins.