吗氯贝胺衍生物的设计、分子对接、合成及抗抑郁活性

Design, Synthesis and Antidepressant Activity of Moclobemide Derivatives

关键词:  吗氯贝胺衍生物  合成  强迫游泳  抗抑郁活性

Key words:  moclobemide derivatives  synthesis  forced swimming  antidepressant activity: moclobemide derivatives  synthesis  forced swimming  antidepressant activity

摘要:

目的 合成了6个新型的吗氯贝胺衍生物并进行了药理活性研究。方法 基于吗氯贝胺为先导化合物,运用分子对接技术设计并筛选出具有良好结合活性的衍生物。以溴代芳基丙酮、氨基丙醇与芳基甲酰氯为原料,通过胺化反应、Leuckart-wallach还原反应、酸化反应和酰化反应,合成了6个新型化合物,采用小鼠强迫游泳实验对目标化合物进行抗抑郁活性研究。结果? 目标化合物通过1H NMR、13C NMR、IR及MS验证了结构,化合物5a、5b小鼠强迫游泳不动时间分别为56.8±15.2 s及47.2±13.1 s,显著低于空白对照组154.6±37.2 s(P<0.05),与吗氯贝胺小鼠强迫游泳不动时间45.7±12.7 s相当。结论 目标化合物5a、5b显示出较好的抗抑郁活性。

Abstract:

OBJECTIVE Six novel morpholino derivatives were synthesized and pharmacological activity studies were performed. METHODS Based on moclobemide as the lead compound, the derivatives with good binding activity were designed and screened using molecular docking technique. Six novel compounds were synthesized by amination, Leuckart-wallach reduction, acidification and acylation reactions using brominated aryl acetone, aminopropanol and aryl carbonyl chloride as raw materials, and the target compounds were investigated for antidepressant activity using forced swimming assay in mice. METHODS Based on moclobemide as the lead compound, the derivatives with good binding activity were designed and screened using molecular docking technique. Six novel compounds were synthesized by amination, Leuckart-wallach reduction, acidification and acylation reactions using brominated aryl acetone, aminopropanol and aryl carbonyl chloride as raw materials, and the target compounds were investigated for antidepressant activity using forced swimming assay in mice. RESULTS The target compounds were structurally verified by 1H NMR, 13C NMR, IR and MS, and the forced swimming immobility time in mice for compounds 5a and 5b was 56.8±15.2 s and 47.2±13.1 s, respectively, which was significantly lower than that of the blank control 154.6±37.2 s (P<0.05), and was comparable to the forced swimming immobility time in mice for morpholino 45.7±12.7 s comparable. CONCLUSION The synthetic route had mild and easy reaction conditions, and the target compounds 5a and 5b showed good antidepressant activity.