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J Med Chem. 2016 Jan 28;59(2):531-44. doi: 10.1021/acs.jmedchem.5b00894. Epub 2016 Jan 7.

Versatility of the Curcumin Scaffold: Discovery of Potent and Balanced Dual BACE-1 and GSK-3β Inhibitors.

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Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna , Via Belmeloro 6, 40126 Bologna, Italy.
Department for Life Quality Studies, Alma Mater Studiorum - University of Bologna , Corso D'Augusto 237, 47921 Rimini, Italy.
Istituto Italiano di Tecnologia , D3, via Morego 30, 16163 Genova, Italy.
Centro de Investigaciones Biologicas, CSIC , Ramiro de Maetzu 9, 28040 Madrid, Spain.


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.

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