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.

DOI: 10.1021/acs.jmedchem.5b00894
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@article{Martino2016VersatilityOT, title={Versatility of the Curcumin Scaffold: Discovery of Potent and Balanced Dual BACE-1 and GSK-3β Inhibitors.}, author={Rita Maria Concetta Di Martino and Angela De Simone and Vincenza Andrisano and Paola Bisignano and Alessandra Bisi and Silvia Gobbi and Angela Rampa and Romana Fato and Christian Bergamini and Daniel I Perez and Ana Mart{\'i}nez and Giovanni Bottegoni and Andrea Cavalli and Federica Belluti}, journal={Journal of medicinal chemistry}, year={2016}, volume={59 2}, pages={531-44} }