Bridging the gap with amide linkers: rational design, synthesis, and multi-target evaluation of sulfonamide/acetamide-NSAID hybrids as dual COX-2/5-LOX inhibitors

Novel hybrids of ibuprofen and naproxen were designed as dual COX-2/5-LOX inhibitors to create safer anti-inflammatory drugs. The prodrugs were developed through a hybridization molecular approach; their potency against COX-1, COX-2, and 5-LOX was assessed, alongside measurements of PGE2 levels, NO scavenging, and mTOR and Nrf2 protein expression. Molecular docking was used to predict binding interactions. Hybrids 9 and 10 showed excellent COX-2 inhibition with IC50 values of 3.3 and 2.0 µM, respectively, and high selectivity indices (SI) of 20.7 and 17.2. Both hybrids also demonstrated substantial 5-LOX inhibition with IC50 values of 3.1 and 4.2 µM. The new hybrids exhibit strong COX-2/5-LOX inhibition, suggesting their structural framework is crucial for developing safer anti-inflammatory drugs.