Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, India.
Department of Pharmaceutical Sciences and Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda 151001, Punjab, India.
Molecules. 2023 Sep 12;28(18):6579. doi: 10.3390/molecules28186579.
No drug on the market, as a single entity, participates in different pathways involved in the pathology of Alzheimer's disease. The current study is aimed at the exploration of multifunctional chalcone derivatives which can act on multiple targets involved in Alzheimer's disease. A series of novel aminoethyl-substituted chalcones have been developed using in silico approaches (scaffold morphing, molecular docking, and ADME) and reported synthetic methods. The synthesized analogs were characterized and evaluated biologically using different in vitro assays against AChE, AGEs, and radical formation. Among all compounds, compound was found to have potent AChE inhibitory activity (IC = 15.3 nM), even more than the standard drug (IC = 15.68 nM). Further, the in vivo evaluation of against STZ-induced dementia in rats showed memory improvement (Morris Water Maze test) in rats. Also, inhibited STZ-induced brain AChE activity and oxidative stress, further strengthening the observed in vitro effects. Further, the molecular dynamic simulation studies displayed the stability of the and AChE complex. The novel aminoethyl-substituted chalcones might be considered potential multifunctional anti-Alzheimer's molecules.
目前市场上还没有一种药物能够作为单一实体参与阿尔茨海默病病理过程中的不同途径。本研究旨在探索能够针对阿尔茨海默病多个靶点的多功能查尔酮衍生物。我们采用基于计算机的方法（支架变形、分子对接和 ADME）和报道的合成方法，开发了一系列新型的氨基乙基取代查尔酮。通过不同的体外 AChE、AGEs 和自由基形成测定法，对合成的类似物进行了特征和生物学评估。在所有化合物中，化合物 表现出很强的 AChE 抑制活性（IC = 15.3 nM），甚至超过了标准药物（IC = 15.68 nM）。此外， 在 STZ 诱导的大鼠痴呆模型中的体内评价表明，该化合物可改善大鼠的记忆（Morris 水迷宫测试）。此外， 还抑制了 STZ 诱导的大脑 AChE 活性和氧化应激，进一步证实了观察到的体外作用。此外，分子动力学模拟研究显示了 与 AChE 复合物的稳定性。新型氨基乙基取代查尔酮可能被认为是具有潜力的多功能抗阿尔茨海默病分子。
