Neurochemical Research ( IF 3.7 ) Pub Date : 2020-10-20 , DOI: 10.1007/s11064-020-03148-2 Cindy Juliet Cristancho Ortiz 1 , Caio Miranda Damasio 1 , Letizia Pruccoli 2 , Nathália Fonseca Nadur 3 , Luciana Luiza de Azevedo 3 , Isabella Alvim Guedes 4 , Laurent Emmanuel Dardenne 4 , Arthur Eugen Kümmerle 3 , Andrea Tarozzi 2 , Claudio Viegas 1
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Abstract
A new series of ten multifunctional Cinnamoyl-N-acylhydrazone-donepezil hybrids was synthesized and evaluated as multifunctional ligands against neurodegenerative diseases. The molecular hybridization approach was based on the combination of 1-benzyl-4-piperidine fragment from the anti-Alzheimer AChE inhibitor donepezil (1) and the cinnamoyl subunit from curcumin (2), a natural product with remarkable antioxidant, neuroprotective and anti-inflammatory properties, using a N-acylhydrazone fragment as a spacer subunit. Compounds 4a and 4d showed moderate inhibitory activity towards AChE with IC50 values of 13.04 and 9.1 µM, respectively. In addition, compound 4a and 4d showed a similar predicted binding mode to that observed for donepezil in the molecular docking studies. On the other hand, compounds 4a and 4c exhibited significant radical scavenging activity, showing the best effects on the DPPH test and also exhibited a significant protective neuronal cell viability exposed to t-BuOOH and against 6-OHDA insult to prevent the oxidative stress in Parkinson’s disease. Similarly, compound 4c was capable to prevent the ROS formation, with indirect antioxidant activity increasing intracellular GSH levels and the ability to counteract the neurotoxicity induced by both OAβ1-42 and 3-NP. In addition, ADMET in silico prediction indicated that both compounds 4a and 4c did not show relevant toxic effects. Due to their above-mentioned biological properties, compounds 4a and 4c could be explored as lead compounds in search of more effective and low toxic small molecules with multiple neuroprotective effects for neurodegenerative diseases.
Graphic Abstract
中文翻译：
肉桂酰基-N-酰基hydr-Donepezil杂种：合成和抗神经退行性疾病的新型多功能配体的评价。
摘要
合成了一系列新的十个多功能肉桂酸-N-酰基ep-多奈哌齐杂种，并将其评价为对抗神经变性疾病的多功能配体。分子杂交方法基于抗阿尔茨海默氏病AChE抑制剂多奈哌齐（1）的1-苄基-4-哌啶片段和姜黄素（2）的肉桂酰亚基的组合，姜黄素是具有显着抗氧化剂，神经保护和抗衰老作用的天然产物。N-酰基hydr片段作为间隔子亚基，具有炎性特性。化合物4a和4d对AChE表现出中等抑制作用，IC 50值分别为13.04和9.1 µM。另外，复合图4a和4d显示了与在分子对接研究中观察到的多奈哌齐相似的预测结合模式。另一方面，化合物4a和4c表现出显着的自由基清除活性，对DPPH测试显示出最佳效果，并且还表现出显着的保护性神经元细胞活力，其暴露于t-BuOOH和针对6-OHDA的损伤可防止帕金森氏病的氧化应激疾病。类似地，化合物4c能够防止ROS形成，间接的抗氧化剂活性增加了细胞内GSH水平，并且具有抵消由OAβ1-42和3-NP诱导的神经毒性的能力。此外，ADMET在计算机模拟中表明两种化合物4a和4c没有显示相关的毒性作用。由于它们的上述生物学特性，可以将化合物4a和4c用作先导化合物，以寻找对神经变性疾病具有多重神经保护作用的更有效和低毒的小分子。
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