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

Research output: Contribution to journalArticlepeer-review

Authors

  • 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
  • Andrea Cavalli
  • Federica Belluti

Colleges, School and Institutes

External organisations

  • Università di Bologna
  • Istituto Italiano di Tecnologia
  • Consejo Superior de Investigaciones Científicas

Abstract

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.

Details

Original languageEnglish
Pages (from-to)531-544
Number of pages14
JournalJournal of Medicinal Chemistry
Volume59
Issue number2
Early online date22 Dec 2015
Publication statusPublished - 28 Jan 2016

ASJC Scopus subject areas