Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El Aini street, P.O. Box 11562, Cairo, Egypt.
Eur J Med Chem. 2011 Feb;46(2):647-58. doi: 10.1016/j.ejmech.2010.11.045. Epub 2010 Dec 8.
Three series of new 2-[(4-substituted piperazin-1-yl) methyl]quinazolin-4(3H)-ones 4a-c, Ethyl 6,7-dimethoxy-4-oxo-3-[2-(4-substituted piperazin-1-yl)acetamido/propanamido]-3,4-dihydroquinazoline-2-carboxylates 9a-f and their 2-methyl analogues 13a-l were designed and synthesized as promising α1-adrenoceptor antagonists. The final compounds were evaluated for their in vivo hypotensive activity in normotensive cats. The most potent hypotensive quinazolinone derivatives 4b, 9e, 13i, 13j were further tested on isolated thoracic aortic rings of male Wister rats. All the tested compounds displayed α1-blocking activity with IC50 ranging from 0.2 to 0.4 mM less than prazosin. Furthermore, in the present work, molecular modeling study using Accelrys Discovery Studio 2.1 software was performed by mapping the synthesized compounds to the α1-adrenoceptor antagonist hypothesis in order to predict their mechanism of action. Compound 13j which has the best-fitting score displayed the highest in vivo and in vitro activity among the tested compounds.
设计并合成了三个系列的新型 2-[(4-取代哌嗪-1-基)甲基]喹唑啉-4(3H)-酮 4a-c、乙基 6,7-二甲氧基-4-氧代-3-[2-(4-取代哌嗪-1-基)乙酰胺基/丙酰胺基]-3,4-二氢喹唑啉-2-羧酸酯 9a-f 及其 2-甲基类似物 13a-l，作为有前途的α1-肾上腺素受体拮抗剂。将最终化合物在正常血压的猫体内进行了体内降压活性评估。最有效的降压喹唑啉酮衍生物 4b、9e、13i、13j 进一步在雄性 Wistar 大鼠的离体胸主动脉环上进行了测试。所有测试的化合物均表现出 α1 阻断活性，IC50 均小于 0.2 至 0.4mM 的哌唑嗪。此外，在本工作中，使用 Accelrys Discovery Studio 2.1 软件进行了分子建模研究，通过将合成的化合物映射到α1-肾上腺素受体拮抗剂假说，以预测其作用机制。在测试的化合物中，具有最佳拟合分数的化合物 13j 表现出最高的体内和体外活性。
