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

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.