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Design, Synthesis, and Evaluation of 2‐Amino‐6‐nitrobenzothiazole‐Derived Hydrazones as MAO Inhibitors: Role of the Methylene Spacer Group
ChemMedChem ( IF 3.6 ) Pub Date : 2016-06-22 , DOI: 10.1002/cmdc.201600202 Rati K. P. Tripathi 1 , Senthil R. Ayyannan 1
ChemMedChem ( IF 3.6 ) Pub Date : 2016-06-22 , DOI: 10.1002/cmdc.201600202 Rati K. P. Tripathi 1 , Senthil R. Ayyannan 1
Affiliation
A series of 2‐amino‐6‐nitrobenzothiazole‐derived extended hydrazones were designed, synthesized, and investigated for their ability to inhibit monoamine oxidase A and B (MAO‐A/MAO‐B). The compounds were found to exhibit inhibitory activities in the nanomolar to micromolar range. Some of the compounds showed excellent potency and selectivity against the MAO‐B isoform. N′‐(5‐Chloro‐2‐oxoindolin‐3‐ylidene)‐2‐(6‐nitrobenzothiazol‐2‐ylamino)acetohydrazide (compound 31) showed the highest MAO‐B inhibitory activity (IC50=1.8±0.3 nm, selectivity index [SI]=766.67), whereas compound 6 [N′‐(1‐(4‐bromophenyl)ethylidene)‐2‐(6‐nitrobenzothiazol‐2‐ylamino)acetohydrazide] was found to be the most active MAO‐A inhibitor (IC50=0.42±0.003 μm). Kinetic studies revealed that compounds 6 and 31 exhibit competitive‐type reversible inhibition against both MAO‐A and MAO‐B, respectively. Structure–activity relationship (SAR) studies disclosed several structural aspects significant for potency and the contribution of the methylene spacer toward MAO‐B inhibitory potency, with minimal or no neurotoxicity. Molecular modeling studies yielded a good correlation between experimental and theoretical inhibitory data. Binding pose analysis revealed the significance of cumulative effects of π–π stacking and hydrogen bond interactions for effective stabilization of virtual ligand–protein complexes. Further optimization studies of compound 31, including co‐crystallization of inhibitor–MAO‐B complexes, are essential to develop these compounds as potential therapeutic agents for MAO‐B‐associated neurodegenerative diseases.
中文翻译:
设计,合成和评估2-氨基-6-硝基苯并噻唑衍生的Hy作为MAO抑制剂:亚甲基间隔基的作用
设计,合成并研究了一系列2-氨基-6-硝基苯并噻唑衍生的扩展,它们抑制单胺氧化酶A和B(MAO-A / MAO-B)的能力。发现该化合物在纳摩尔至微摩尔范围内表现出抑制活性。一些化合物对MAO-B同工型具有出色的效价和选择性。N ′(5-氯-2-氧代吲哚-3-亚基)-2-(6-硝基苯并噻唑-2-基氨基)乙酰肼(化合物31)显示出最高的MAO-B抑制活性(IC 50 = 1.8±0.3 n m,选择性指数[SI] = 766.67),而化合物6 [ N' - (1-(4-溴苯基)亚乙基)-2-(6-硝基苯-2-基氨基)乙酰肼]被发现是最活跃的MAO-A抑制剂(IC 50 = 0.42±0.003μ米)。动力学研究表明,化合物6和31对MAO-A和MAO-B分别表现出竞争性可逆抑制作用。结构-活性关系(SAR)研究揭示了几个结构方面,这些结构方面对效能和亚甲基间隔基对MAO-B抑制效能的影响均具有重要意义,而对神经毒性的影响很小或没有。分子建模研究在实验和理论抑制数据之间产生了良好的相关性。结合姿势分析揭示了π-π堆积和氢键相互作用的累积效应对于有效稳定虚拟配体-蛋白质复合物的重要性。化合物31的进一步优化研究包括抑制剂-MAO-B复合物的共结晶,对于开发这些化合物作为与MAO-B相关的神经退行性疾病的潜在治疗剂至关重要。
更新日期:2016-06-22
中文翻译:
![](https://scdn.x-mol.com/jcss/images/paperTranslation.png)
设计,合成和评估2-氨基-6-硝基苯并噻唑衍生的Hy作为MAO抑制剂:亚甲基间隔基的作用
设计,合成并研究了一系列2-氨基-6-硝基苯并噻唑衍生的扩展,它们抑制单胺氧化酶A和B(MAO-A / MAO-B)的能力。发现该化合物在纳摩尔至微摩尔范围内表现出抑制活性。一些化合物对MAO-B同工型具有出色的效价和选择性。N ′(5-氯-2-氧代吲哚-3-亚基)-2-(6-硝基苯并噻唑-2-基氨基)乙酰肼(化合物31)显示出最高的MAO-B抑制活性(IC 50 = 1.8±0.3 n m,选择性指数[SI] = 766.67),而化合物6 [ N' - (1-(4-溴苯基)亚乙基)-2-(6-硝基苯-2-基氨基)乙酰肼]被发现是最活跃的MAO-A抑制剂(IC 50 = 0.42±0.003μ米)。动力学研究表明,化合物6和31对MAO-A和MAO-B分别表现出竞争性可逆抑制作用。结构-活性关系(SAR)研究揭示了几个结构方面,这些结构方面对效能和亚甲基间隔基对MAO-B抑制效能的影响均具有重要意义,而对神经毒性的影响很小或没有。分子建模研究在实验和理论抑制数据之间产生了良好的相关性。结合姿势分析揭示了π-π堆积和氢键相互作用的累积效应对于有效稳定虚拟配体-蛋白质复合物的重要性。化合物31的进一步优化研究包括抑制剂-MAO-B复合物的共结晶,对于开发这些化合物作为与MAO-B相关的神经退行性疾病的潜在治疗剂至关重要。