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

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

60 Citations (Scopus)


The multitarget approach has gained increasing acceptance as a useful tool to address complex and multifactorial maladies such as Alzheimeŕs 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.

Original languageEnglish
Pages (from-to)531-544
Number of pages14
JournalJournal of Medicinal Chemistry
Issue number2
Early online date22 Dec 2015
Publication statusPublished - 28 Jan 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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