Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr Elini St., Cairo 11562, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Badr University in Cairo, Badr City, Cairo 11829, Egypt.
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr Elini St., Cairo 11562, Egypt.
Eur J Med Chem. 2019 Jun 1;171:332-342. doi: 10.1016/j.ejmech.2019.03.052. Epub 2019 Mar 23.
New pyrazole derivatives 2-5 were synthesized and evaluated for their COX-1 and COX-2 inhibitory activity in vitro. All compounds showed good inhibitory activity at a nanomolar level and most compounds exhibited selectivity towards COX-2 inhibition. Compounds 2a, 3b, 4a, 5b and 5e exhibited IC towards COX-2 enzyme of 19.87, 39.43, 61.24, 38.73 and 39.14 nM, respectively. Furthermore, compounds 3b, 4a, 5b and 5e exhibited a selectivity index of 22.21, 14.35, 17.47 and 13.10, respectively. The most active compounds were further subjected to in vivo anti-inflammatory assay. The tested compounds showed better or comparable activity to celecoxib as positive control. In order to explore their binding mode and selectivity behaviour, molecular docking in the active site of COX-2 was carried out for these derivatives. Analysis of the docked poses of the compounds showed that they adopt similar conformations to the highly selective COX-2 inhibitor, SC-558. The docking pose of compound 3b was confirmed by molecular dynamics. All the tested compounds exhibited potent inhibitory effect on the production of PGE, in addition to their inhibition of COX-2 enzyme.
新的吡唑衍生物 2-5 被合成并评估其在体外的 COX-1 和 COX-2 抑制活性。所有化合物在纳摩尔水平均显示出良好的抑制活性，并且大多数化合物对 COX-2 抑制具有选择性。化合物 2a、3b、4a、5b 和 5e 对 COX-2 酶的 IC 分别为 19.87、39.43、61.24、38.73 和 39.14nM。此外，化合物 3b、4a、5b 和 5e 的选择性指数分别为 22.21、14.35、17.47 和 13.10。最活跃的化合物进一步进行了体内抗炎测定。测试的化合物表现出与阳性对照塞来昔布相当或更好的活性。为了探索它们的结合模式和选择性行为，对这些衍生物在 COX-2 的活性部位进行了分子对接。对化合物对接构象的分析表明，它们采用与高度选择性 COX-2 抑制剂 SC-558 相似的构象。化合物 3b 的对接构象通过分子动力学得到了证实。除了抑制 COX-2 酶外，所有测试的化合物均对 PGE 的产生具有很强的抑制作用。
