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Novel N-Substituted 5-aminosalicylamides as Dual Inhibitors of Cyclooxygenase and 5-Lipoxygenase Enzymes: Synthesis, Biological Evaluation and Docking Study

مؤلف البحث
Mohamed K.S. El-Nagar, Hajjaj H.M. Abdu-Allah, Ola I.A. Salem, Abdel-Hamid N. Kafafy and Hanan S.M. Farghaly
مجلة البحث
Bioorganic Chemistry
الناشر
NULL
تصنيف البحث
1
عدد البحث
Vol. 78
موقع البحث
https://doi.org/10.1016/j.bioorg.2018.02.023
سنة البحث
2018
المشارك في البحث
ملخص البحث

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, 1H NMR, 13C 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 (IC50 = 0.10 µM) with significant COX-2 selectivity indices (SI = 135 & 145 respectively) approximate to celecoxib (IC50 = 0.049 µM, SI = 308.16) and exceeding indomethacin (IC50 = 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 (IC50 = 3.41 µM) relative to zileuton (IC50 = 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.