Versatility of the Curcumin Scaffold: Discovery of Potent and Balanced Dual BACE-1 and GSK-3β Inhibitors
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- 作者：Rita Maria Concetta Di Martino ; Angela De Simone ; Vincenza Andrisano ; Paola Bisignano ; Alessandra Bisi ; Silvia Gobbi ; Angela Rampa ; Romana Fato ; Christian Bergamini ; Daniel I. Perez ; Ana Martinez ; Giovanni Bottegoni ; Andrea Cavalli ; Federica Belluti
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：January 28, 2016
- 年：2016
- 卷：59
- 期：2
- 页码：531-544
- 全文大小：597K
- ISSN：1520-4804
文摘
The multitarget approach has gained increasing acceptance as a useful tool to address complex and multifactorial maladies such as Alzheimer’s disease (AD). The concurrent inhibition of the validated AD targets β-secretase (BACE-1) and glycogen synthase kinase-3β (GSK-3β) by attacking both β-amyloid and tau protein cascades has been identified as a promising AD therapeutic strategy. In our study, curcumin was identified as a lead compound for the simultaneous inhibition of both targets; therefore, synthetic efforts were dedicated to obtaining a small library of novel curcumin-based analogues, and a number of potent and balanced dual-target inhibitors were obtained. In particular, 2, 6, and 7 emerged as promising drug candidates endowed with neuroprotective potential and brain permeability. Notably, for some new compounds the symmetrical diketo and the β-keto–enol tautomeric forms were purposely isolated and tested in vitro, allowing us to gain insight into the key requirements for BACE-1 and GSK-3β inhibition.