El-Miligy Mostafa Mm, Hazzaa Aly A, El-Messmary Hanan, Nassra Rasha A, El-Hawash Soad Am
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
Faculty of Pharmacy, Omar-Almukhtar University, Libya.
Future Med Chem. 2017 Apr;9(5):443-468. doi: 10.4155/fmc-2016-0230. Epub 2017 Mar 31.
Simultaneous inhibition of 5-LOX/COX may enhance anti-inflammatory effects and reduce side effects. Hence, synthesis of novel dual inhibitors of 5-LOX/COX is an important strategy for treatment of inflammation. Results/methodology: The target compounds were designed to hybridize benzothiophene scaffold or its bioisostere benzofuran with various anti-inflammatory pharmacophore hetercycles through different atoms spacers. Compounds 4a, 4c, 4d, 5b, 7a, showed significant in vitro LOX inhibitory activity higher than that of meclofenamate sodium. Compounds 4b, 4e, 4f, 5a exhibited significant in vitro COX-2 inhibition higher than celecoxib and in vitro LOX inhibitory activity twice that of reference. These compounds elicited significant in vivo anti-inflammatory activities higher than celecoxib in formalin-induced paw edema test. Compound 4e exhibited gastrointestinal safety profile as celecoxib. The results were also consistent with the docking studies.
Compound 4e could be considered as structural lead for the development of a new class of anti-inflammatory agents with better safety profile.
同时抑制5-脂氧合酶（5-LOX）/环氧化酶（COX）可能增强抗炎作用并减少副作用。因此，合成新型5-LOX/COX双重抑制剂是治疗炎症的重要策略。结果/方法：通过不同的原子间隔基，将目标化合物设计为苯并噻吩骨架或其生物电子等排体苯并呋喃与各种抗炎药效团杂环杂交。化合物4a、4c、4d、5b、7a在体外显示出显著的脂氧合酶抑制活性，高于甲氯芬那酸钠。化合物4b、4e、4f、5a在体外显示出高于塞来昔布的显著COX-2抑制活性，且体外脂氧合酶抑制活性是参比物的两倍。在福尔马林诱导的爪肿胀试验中，这些化合物表现出高于塞来昔布的显著体内抗炎活性。化合物4e表现出与塞来昔布一样的胃肠道安全性。结果也与对接研究一致。
化合物4e可被视为开发具有更好安全性的新型抗炎药的结构先导物。
