Abstract

The multitarget approach has gained increasing acceptance as a useful tool to address complex and multifactorial maladies such as Alzheimers disease (AD). The concurrent inhibition of the validated AD targets beta-secretase (BACE-1) and glycogen synthase kinase-3 beta (GSK-3 beta) by attacking both beta-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 beta-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-3 beta inhibition.