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Novel 1,3,4-thiadiazole compounds as potential MAO-A inhibitors – design, synthesis, biological evaluation and molecular modelling
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2020-08-18 , DOI: 10.1039/d0md00150c Begüm Nurpelin Sağlık 1, 2 , Betül Kaya Çavuşoğlu 2, 3 , Ulviye Acar Çevik 1, 2 , Derya Osmaniye 1, 2 , Serkan Levent 1, 2 , Yusuf Özkay 1, 2 , Zafer Asım Kaplancıklı 1
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2020-08-18 , DOI: 10.1039/d0md00150c Begüm Nurpelin Sağlık 1, 2 , Betül Kaya Çavuşoğlu 2, 3 , Ulviye Acar Çevik 1, 2 , Derya Osmaniye 1, 2 , Serkan Levent 1, 2 , Yusuf Özkay 1, 2 , Zafer Asım Kaplancıklı 1
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Monoamine oxidases (MAOs) are important drug targets for the management of neurological disorders. Herein, a series of new 1,3,4-thiadiazole derivatives bearing various alkyl/arylamine moieties as MAO inhibitors were designed and synthesized. All of the compounds were more selective against hMAO-A than hMAO-B. The half maximal inhibitory concentration (IC50) values of most of the compounds were lower than that of the common drug moclobemide (IC50 = 4.664 μM) and compound 6b was proven to be the most active compound (IC50 = 0.060 μM). Moreover, it was seen that compound 6b showed a similar inhibition profile to that of clorgyline (IC50 = 0.048 μM). The inhibition profile was found to be reversible and competitive for compound 6b with MAO-A selectivity. Molecular modelling studies aided in the understanding of the interaction modes between compound 6b and MAO-A. Furthermore, this compound was predicted to have a good pharmacokinetic profile and high BBB penetration. Therefore, such compounds are of interest towards developing new MAO inhibitors.
中文翻译：
新型 1,3,4-噻二唑化合物作为潜在的 MAO-A 抑制剂——设计、合成、生物学评价和分子建模
单胺氧化酶 (MAO) 是治疗神经系统疾病的重要药物靶点。在此，我们设计并合成了一系列新型 1,3,4-噻二唑衍生物，这些衍生物具有各种烷基/芳胺部分作为 MAO 抑制剂。所有化合物对h MAO-A 的选择性均高于h MAO-B。大多数化合物的半数最大抑制浓度（IC 50）值低于常用药物吗氯贝胺（IC 50 = 4.664 μM），化合物6b被证明是最有效的化合物（IC 50 = 0.060 μM）。此外，可以看出化合物6b显示出与 clorgyline 相似的抑制特性（IC 50= 0.048 微米）。发现抑制谱对于具有 MAO-A 选择性的化合物6b是可逆的和竞争性的。分子模型研究有助于理解化合物6b和 MAO-A 之间的相互作用模式。此外，预计该化合物具有良好的药代动力学特征和高 BBB 渗透性。因此，此类化合物对开发新的 MAO 抑制剂具有重要意义。
更新日期：2020-09-23
中文翻译：
新型 1,3,4-噻二唑化合物作为潜在的 MAO-A 抑制剂——设计、合成、生物学评价和分子建模
单胺氧化酶 (MAO) 是治疗神经系统疾病的重要药物靶点。在此，我们设计并合成了一系列新型 1,3,4-噻二唑衍生物，这些衍生物具有各种烷基/芳胺部分作为 MAO 抑制剂。所有化合物对h MAO-A 的选择性均高于h MAO-B。大多数化合物的半数最大抑制浓度（IC 50）值低于常用药物吗氯贝胺（IC 50 = 4.664 μM），化合物6b被证明是最有效的化合物（IC 50 = 0.060 μM）。此外，可以看出化合物6b显示出与 clorgyline 相似的抑制特性（IC 50= 0.048 微米）。发现抑制谱对于具有 MAO-A 选择性的化合物6b是可逆的和竞争性的。分子模型研究有助于理解化合物6b和 MAO-A 之间的相互作用模式。此外，预计该化合物具有良好的药代动力学特征和高 BBB 渗透性。因此，此类化合物对开发新的 MAO 抑制剂具有重要意义。
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