Design, synthesis and biological evaluation of 2,3-dihydro-5,6-dimethoxy-1H-inden-1-one and piperazinium salt hybrid derivatives as hAChE and hBuChE enzyme inhibitors.,European Journal of Medicinal Chemistry

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Design, synthesis and biological evaluation of 2,3-dihydro-5,6-dimethoxy-1H-inden-1-one and piperazinium salt hybrid derivatives as hAChE and hBuChE enzyme inhibitors.
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-02-13 , DOI: 10.1016/j.ejmech.2020.112140
Sakineh Mozaffarnia ₁ , Reza Teimuri-Mofrad ₂ , Mohammad-Reza Rashidi ₃

Affiliation

2,3-Dihydro-5,6-dimethoxy-2-[4-(4-alkyl-4-methylpiperazinium-1-yl)benzylidine]-1H-inden-1-one halide salt derivatives as a novel donepezil hybrid analogs with the property of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzyme inhibition were designed and synthesized via N-alkylation reaction of 2,3-dihydro-5,6-dimethoxy-2-[4-(4-methylpiperazin-1-yl)benzylidene]-1H-inden-1-one with some alkyl halides. Biological tests demonstrated that most of the synthesized compounds have moderate to good inhibitory activities effect on cholinesterase enzymes. Among them, 10e showed the best profile as a selected compound for inhibition of hAChE (IC50 = 0.32) and hBuChE (IC50 = 0.43 μM) enzymes. Kinetic analysis and molecular docking led to a better understanding of this compound. Kinetic studies disclosed that 10e inhibited acetylcholinesterase in mixed-type and butyrylcholinesterase in non-competitive type. The toxicity results showed that 10e is less toxic than donepezil and has better inhibitory activity against hBuChE when compared to donepezil or Galantamine. Other performed experiments revealed that 10e has an anti-β amyloid effect which is capable of reducing ROS, LDH and MDA also possing positive effect on TAC. On the other hand, it has shown a good anti-inflammation effect.

中文翻译：

设计，合成和生物学评估作为hAChE和hBuChE酶抑制剂的2,3-二氢-5,6-二甲氧基-1H-茚满1-和哌嗪鎓盐杂合衍生物。

2,3-二氢-5,6-二甲氧基-2- [4-（4-烷基-4-甲基哌嗪-1-基）苄基] -1H-茚-1-卤化物盐衍生物作为新型多奈哌齐杂合体通过2,3-二氢-5,6-二甲氧基-2- [4-（4-甲基哌嗪-1-基）的N-烷基化反应，设计合成了乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）的酶抑制特性。亚苄基] -1H-茚-1-酮与一些烷基卤化物。生物学测试表明，大多数合成的化合物对胆碱酯酶具有中等至良好的抑制活性。其中，10e显示出最佳的抑制hAChE（IC50 = 0.32）和hBuChE（IC50 = 0.43μM）酶的特性。动力学分析和分子对接使人们对该化合物有了更好的了解。动力学研究表明，10e可抑制混合型乙酰胆碱酯酶，而非竞争型可抑制丁酰胆碱酯酶。毒性结果表明，与多奈哌齐或加兰他敏相比，10e的毒性比多奈哌齐低，并且对hBuChE具有更好的抑制活性。其他进行的实验表明，10e具有抗β淀粉样蛋白的作用，能够减少ROS，LDH和MDA，也对TAC发挥积极作用。另一方面，它显示出良好的抗炎作用。LDH和MDA也对TAC具有积极作用。另一方面，它显示出良好的抗炎作用。LDH和MDA也对TAC具有积极作用。另一方面，它显示出良好的抗炎作用。

更新日期：2020-02-20

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