Novel N-substituted 5-aminosalicylamides as dual inhibitors of cyclooxygenase and 5-lipoxygenase enzymes: Synthesis, biological evaluation and docking study

Abstract Three new series of 5-aminosalicylic acid derivatives; series I ( 14 , 16 – 18 ), series II ( 19 – 30 ) and series III ( 31 – 41 ) were synthesized as potential dual COX-2/5-LOX inhibitors. Their chemical structures were confirmed using spectroscopic tools including IR, 1 H NMR, 13 C NMR, mass spectroscopy and elemental analyses. The anti-inflammatory activity for all target compounds was evaluated in vivo using carrageenan-induced paw edema. Compound 36 showed the highest anti-inflammatory activity (114.12%) relative to reference drug indomethacin at 4 h interval. Selected derivatives were evaluated in vitro to inhibit ovine COX-1, human recombinant COX-2 and 5-LOX enzymes. Compounds 34 & 35 exhibited significant COX-2 inhibition (IC 50  = 0.10 µM) with significant COX-2 selectivity indices (SI = 135 & 145 respectively) approximate to celecoxib (IC 50  = 0.049 µM, SI = 308.16) and exceeding indomethacin (IC 50  = 0.51 µM, SI = 0.08). Interestingly, all compounds showed superior 5-LOX inhibitory activity about 2–5 times relative to zileuton . Compound 16 was the superlative 5-LOX inhibitor that revealed (IC 50  = 3.41 µM) relative to zileuton (IC 50  = 15.6 µM). Compounds 34 , 35 , 36 and 41 showed significant dual COX-2/5-LOX inhibitions. The gastric ulcerogenic effect of compound 36 was examined on gastric mucosa of albino rats and they showed superior GI safety profile compared with indomethacin . Molecular docking studies of the compounds into the binding sites of COX-1, COX-2 and 5-LOX allowed us to shed light on the binding mode of these novels dual COX and 5-LOX inhibitors.