Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Beirut Arab University, Beirut, Lebanon.
Department of Pharmaceutical Sciences, Faculty of Pharmacy, Beirut Arab University, Beirut, Lebanon.
J Enzyme Inhib Med Chem. 2022 Dec;37(1):2179-2190. doi: 10.1080/14756366.2022.2109025.
A structure-guided modelling approach using COX-2 as a template was used to investigate the effect of replacing the chloro atom located at the chlorophenyl ring of amide-linked bipyrazole moieties, aiming at attaining better anti-inflammatory effect with a good safety profile. Bromo, fluoro, nitro, and methyl groups were revealed to be ideal candidates. Consequently, new bipyrazole derivatives were synthesised. The inhibitory COX-1/COX-2 activity of the synthesised compounds exhibited promising selectivity. The fluoro and methyl derivatives were the most active candidates. The formalin-induced paw edoema model confirmed the anti-inflammatory activity of the synthesised compounds. All the tested derivatives had a good ulcerogenic safety profile except for the methyl substituted compound. molecular dynamics simulations of the fluoro and methyl poses complexed with COX-2 for 50 ns indicated stable binding to COX-2. Generally, our approach delivers a fruitful matrix for the development of further amide-linked bipyrazole anti-inflammatory candidates.
采用 COX-2 作为模板的结构导向建模方法，研究了取代酰胺连接的双吡唑部分的氯苯基环上的氯原子的效果，旨在获得更好的抗炎效果和良好的安全性。溴代、氟代、硝基和甲基被证明是理想的取代基。因此，新的双吡唑衍生物被合成。所合成化合物的抑制 COX-1/COX-2 活性表现出良好的选择性。氟代和甲基衍生物是最活跃的候选物。福林诱导的爪水肿模型证实了所合成化合物的抗炎活性。除了甲基取代化合物外，所有测试的衍生物都具有良好的致溃疡安全性。与 COX-2 结合 50ns 的氟代和甲基复合物的分子动力学模拟表明与 COX-2 结合稳定。总的来说，我们的方法为进一步开发酰胺连接的双吡唑抗炎候选物提供了一个富有成效的矩阵。
