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首页> 外文期刊>Archiv der Pharmazie >Design, Synthesis, and Docking Study of Pyrimidine-Triazine Hybrids for GABA Estimation in Animal Epilepsy Models
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Design, Synthesis, and Docking Study of Pyrimidine-Triazine Hybrids for GABA Estimation in Animal Epilepsy Models

机译：嘧啶 - 三嗪杂交种对动物癫痫模型GABA估算的设计，合成和对接研究

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摘要

A series of new pyrimidine-triazine hybrids (4a-t) was designed and synthesized, from which potent anticonvulsant agents were identified. Most of the compounds exhibited promising anticonvulsant activity against the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests, along with minimal motor impairment with higher safety compared to the standard drugs, phenytoin and carbamazepine. In the series, 5-(4-(4-fluorophenyl)-6-(4-hydroxyphenyl)-2-thioxo-5,6-dihydropyrimidin-1(2H)-yl)-1,2-dihydro-1,2,4-triazin-3(6H)-one (4o) and 5-(6-(4-hydroxy-3-methoxyphenyl)-4-(4-hydroxyphenyl)-2-thioxo-5,6-dihydropyrimidin-1(2H)-yl)-1,2-dihydro-1,2,4-triazin-3(6H)-one (4s) emerged as most potent anticonvulsant agents with median doses of 22.54 and 29.40mg/kg (MES ED50), 285.02 and 293.42mg/kg (scPTZ ED50), and 389.11 and 412.16mg/kg (TD50), respectively. Docking studies were also performed for all synthesized compounds to get insight into the binding pattern toward the GABA(A) receptor as a possible mechanism of their anticonvulsant action, and in silico ADME studies were carried out to predict the safety and stability of the molecules. The increased GABA level in the experimental animals in the neurochemical estimation assay confirmed their GABAergic modulating activity. The most potent compounds were also evaluated for their neurotoxic and hepatotoxic effects. Fortunately, they did not show any sign of neurotoxicity or hepatotoxicity, suggesting that they have a broad spectrum of anticonvulsant activity with a large safety margin. Together, this research suggested that 4o and 4s may serve as leads in the discovery and development of new anticonvulsant drugs.
机译：设计并合成了一系列新的嘧啶 - 三嗪杂交物（4A-T），从中鉴定了强效抗惊厥药物。大多数化合物表现出对最大电孔（MES）和皮下五苯甲酸四唑（SCPTZ）试验的有前途的抗惊厥活性，与标准药物，苯妥林和卡马祖脂相比具有更高的安全性，具有更高的安全性。在该系列中，5-（4-（4-氟苯基）-6-（4-羟基苯基）-2-硫代-5,6-二氢嘧啶-1（2H） - 酯）-1,2-二氢-1,2 ，4-三嗪-3（6H） - ONE（40）和5-（6-（4-羟基-3-甲氧基苯基）-4-（4-羟基苯基）-2-硫代氧基-5,6-二氢嘧啶-1（ 2H） - 烯基）-1,2-二氢-1,2,4-三嗪-3（6H） - ONE（4S）出现为最有效的抗惊厥药剂，中值22.54和29.40mg / kg（MES ED50）， 285.02和293.42mg / kg（SCPTZ ED50）和389.11和412.16mg / kg（TD50）。对所有合成化合物还对朝向GABA（A）受体的结合模式进行了洞察，作为其抗惊厥作用的可能机制，进行了对接研究，并在硅ADME研究中进行以预测分子的安全性和稳定性。神经化学估计测定中实验动物中的GABA水平增加证实了它们的加布性调节活性。还评估了最有效的化合物的神经毒性和肝毒性作用。幸运的是，他们没有显示出神经毒性或肝毒性的任何迹象，表明它们具有广泛的抗惊厥活性，具有大的安全保证金。这项研究表明，4o和4s可以作为发现和开发新的抗惊厥药物的导致。

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  • 来源
    《Archiv der Pharmazie》 |2017年第9期|共18页
  • 作者

    Sahu Meeta; Siddiqui Nadeem; Naim Mohd. Javed; Alam Ozair; Yar Mohammad Shahar; Sharma Vidushi; Wakode Sharad;

  • 作者单位

    Jamia Hamdard Sch Pharmaceut Educ &

    Res Dept Pharmaceut Chem New Delhi 110062 India;

    Jamia Hamdard Sch Pharmaceut Educ &

    Res Dept Pharmaceut Chem New Delhi 110062 India;

    Jamia Hamdard Sch Pharmaceut Educ &

    Res Dept Pharmaceut Chem New Delhi 110062 India;

    Jamia Hamdard Sch Pharmaceut Educ &

    Res Dept Pharmaceut Chem New Delhi 110062 India;

    Jamia Hamdard Sch Pharmaceut Educ &

    Res Dept Pharmaceut Chem New Delhi 110062 India;

    Delhi Inst Pharmaceut Sci &

    Res DIPSAR Dept Pharmaceut Chem New Delhi India;

    Delhi Inst Pharmaceut Sci &

    Res DIPSAR Dept Pharmaceut Chem New Delhi India;

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  • 原文格式 PDF
  • 正文语种 ger
  • 中图分类 药学;
  • 关键词

    Rational drug design; Structure elucidation; Synthesis;

    机译：合理的药物设计;结构阐明;合成;

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