一种新的基于α-淀粉酶抑制剂的螺环吲哚-吡咯烷棒状硫铬酮-吡喃酮药效团:用分子电子密度理论揭示[3+2]环加成反应。

Mohammad Shahidul Islam, Abdullah Mohammed Al-Majid, Matti Haukka, Zahida Parveen, Nabeela Ravaiz, Abdul Wadood, Ashfaq Ur Rehman, Mar Ríos-Gutiérrez, Luis R. Domingo, Assem Barakat
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引用次数: 2

摘要

以乙烯基硫铬烯和吡唑支架为原料,通过[3+2]环加成(32CA)反应,以仲氨基酸和取代的靛蓝为原料,一步合成了一种新的螺氧吲哚-吡咯烷棒状硫铬烯基序和吡唑基序。用分子电子密度理论研究了AY10与乙烯衍生物6的32CA反应。AY10,N的高亲核性 = 4.39 eV,可以解释最有利的TS on是13.9 kcal mol-1。这种32CA通过非协同一步机制发生,呈现出完全的邻位和内立体选择性,这是由两个分子内H…O氢键的形成控制的。螺环吲哚吡咯烷接枝硫铬酮和吡唑的设计测试了α-淀粉酶的抑制作用,并在纳米级反应范围内显示出高效性。通过分子对接研究了最活跃的杂交种和受体之间的关键相互作用。通过计算机ADMET预测,对所设计的螺环吲哚吡咯烷的理化性质进行了研究。新合成的最有效的杂交体可以被认为是2型糖尿病(T2DM)药物发现开发的先导化合物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A novel alpha-amylase inhibitor-based spirooxindole-pyrrolidine-clubbed thiochromene-pyrzaole pharmacophores: Unveiling the [3+2] cycloaddition reaction by molecular electron density theory

A novel spirooxindole-pyrrolidine clubbed thiochromene and pyrazole motifs were synthesized by [3+2] cycloaddition (32CA) reactions in one step process starting from the ethylene-based thiochromene and pyrazole scaffolds with the secondary amino-acids and substituted isatins in high yield. The 32CA reaction of AY 10 with ethylene derivative 6 has also been studied with Molecular Electron Density Theory. The high nucleophilic character of AY 10, N = 4.39 eV, allows explaining that the most favorable TS-on is 13.9 kcal mol−1 below the separated reagent. This 32CA, which takes place through a non-concerted one-step mechanism, presents a total ortho regio- and endo stereoselectivity, which is controlled by the formation of two intramolecular HO hydrogen bonds. The design of spirooxindole-pyrrolidines engrafted thiochromene and pyrazole was tested for alpha-amylase inhibition and show a high efficacy in nanoscale range of reactivity. The key interaction between the most active hybrids and the receptor was studied by molecular docking. The physiochemical properties of the designed spirooxindole-pyrrolidines were carried out by in silico ADMET prediction. The newly synthesized most potent hybrid could be considered as a lead compound for drug discovery development for type 2 diabetes mellitus (T2DM).

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