Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University, Alexandria 21521, Egypt.
Molecules. 2022 Mar 30;27(7):2240. doi: 10.3390/molecules27072240.
Some new pyrimidine derivatives comprising arylsulfonylhydrazino, ethoxycarbonylhydrazino, thiocarbamoylhydrazino and substituted hydrazone and thiosemicarbazide functionalities were prepared from Biginelli-derived pyrimidine precursors. Heterocyclic ring systems such as pyrazole, pyrazolidinedione, thiazoline and thiazolidinone ring systems were also incorporated into the designed pyrimidine core. Furthermore, fused triazolopyrimidine and pyrimidotriazine ring systems were prepared. The synthesized compounds were evaluated for their calcium channel blocking activity as potential hypotensive agents. Compounds , , , , and showed the highest ex vivo calcium channel blocking activities compared with the reference drug nifedipine. Compounds and were selected for further biological evaluation. They revealed good hypotensive activities following intravenous administration in dogs. Furthermore, and displayed drug-like ADME parameters. A ligand-based pharmacophore model was developed to provide adequate information about the binding mode of the newly synthesized active compounds , , , , and . This may also serve as a reliable basis for designing new active pyrimidine-based calcium channel blockers.
一些包含芳基磺酰基腙、乙氧羰基腙、硫代碳酰肼和取代腙及硫代缩氨基脲官能团的新型嘧啶衍生物是由比格列奈衍生的嘧啶前体制备的。杂环如吡唑、吡唑烷二酮、噻唑啉和噻唑烷酮环系统也被引入到设计的嘧啶核心中。此外，还制备了稠合的三唑并嘧啶和嘧啶并三嗪环系统。合成的化合物被评估为潜在的降压剂的钙通道阻断活性。与参考药物硝苯地平相比，化合物 、 、 、 、 和 表现出最高的体外钙通道阻断活性。化合物 和 被选择进行进一步的生物学评价。它们在狗体内静脉给药后表现出良好的降压活性。此外， 和 表现出类药的 ADME 参数。基于配体的药效团模型被开发出来，为新合成的活性化合物 、 、 、 和 的结合模式提供了充分的信息。这也可能成为设计新的基于嘧啶的钙通道阻滞剂的可靠基础。
