Details

Autor(en) / Beteiligte

• Di Martino, Rita Maria Concetta
• De Simone, Angela
• Andrisano, Vincenza
• Bisignano, Paola
• Bisi, Alessandra
• Gobbi, Silvia
• Rampa, Angela
• Fato, Romana
• Bergamini, Christian
• Perez, Daniel I
• Martinez, Ana
• Bottegoni, Giovanni
• Cavalli, Andrea
• Belluti, Federica

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2016-01, Vol.59 (2), p.531-544

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.