新型苯并[d]噻唑-2-基-氨基乙酰胺作为潜在的抗惊厥药：分子特性的合成、活性和预测,Archiv der Pharmazie

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新型苯并[d]噻唑-2-基-氨基乙酰胺作为潜在的抗惊厥药：分子特性的合成、活性和预测
Archiv der Pharmazie ( IF 4.3 ) Pub Date : 2015-03-17 , DOI: 10.1002/ardp.201400466
Ruhi Ali ₁ , Nadeem Siddiqui

Affiliation

使用具有芳香族疏水芳基的药效特征合成了一系列 N-(取代-2-氧代-4-苯基氮杂环丁烷-1-基)-2-((6-取代苯并[d]噻唑-2-基)氨基)乙酰胺衍生物环（A），NHCO作为氢键域，氮原子作为电子供体（D），苯基作为远端芳环（C）。最初使用最大电休克癫痫 (MES) 试验和皮下戊四唑试验在白化小鼠中筛选合成分子的抗惊厥活性。还使用旋转棒试验对合成分子进行了急性神经毒性研究。这些测试的结果表明，两种化合物 5b 和 5q 在 MES 测试中显示出有希望的活性，ED50 值分别为 15.4 和 18.6 mg/kg，保护指数分别为 20.7 和 34.9，发现它们比标准药物苯妥英 (6.9) 和卡马西平 (8.1) 高约四倍。这些分子可以作为设计方案的引导。使用 Molinspiration 软件估计所有合成化合物的药代动力学特征。这些化合物都没有违反利平斯基的“五法则”。讨论了可能的构效关系。总之，这份手稿表明，开发的模型对于进一步研究更好的苯并噻唑衍生物以供未来发现和开发具有高度的预测能力。这些化合物都没有违反利平斯基的“五法则”。讨论了可能的构效关系。总之，这份手稿表明，开发的模型对于进一步研究更好的苯并噻唑衍生物以供未来发现和开发具有高度的预测能力。这些化合物都没有违反利平斯基的“五法则”。讨论了可能的构效关系。总之，这份手稿表明，开发的模型对于进一步研究更好的苯并噻唑衍生物以供未来发现和开发具有高度的预测能力。

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New Benzo[d]thiazol-2-yl-aminoacetamides as Potential Anticonvulsants: Synthesis, Activity and Prediction of Molecular Properties

A series of N‐(substituted‐2‐oxo‐4‐phenylazetidin‐1‐yl)‐2‐((6‐substitutedbenzo[d]thiazol‐2‐yl)amino)acetamide derivatives were synthesized using pharmacophoric features with aromatic hydrophobic aryl ring (A), NHCO as hydrogen bonding domain, the nitrogen atom as electron donor (D), and phenyl as distal aryl ring (C). The synthesized molecules were initially screened for anticonvulsant activity using the maximal electroshock seizure (MES) test and the subcutaneous pentylenetetrazole test in albino mice. An acute neurotoxicity study on the synthesized molecules was also carried out using the rotarod test. The results of these tests revealed that two compounds, 5b and 5q, showed promising activity with ED50 values of 15.4 and 18.6 mg/kg and protective indices of 20.7 and 34.9 in the MES test, respectively, which are found to be approximately fourfold higher than those of the standard drugs phenytoin (6.9) and carbamazepine (8.1). These molecules may act as lead of the designed scheme. The pharmacokinetic profiles of all the synthesized compounds were estimated using Molinspiration software. None of the compounds violated Lipinski's “rule of five”. The possible structure–activity relationship was discussed. In conclusion, this manuscript shows that the developed model has a highly prognostic power for the further investigation of better benzothiazole derivatives for future discovery and development.

更新日期：2015-03-17

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