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Molecules 2016, 21(5), 643;

Naturally Inspired Molecules as Multifunctional Agents for Alzheimer’s Disease Treatment

Department of Pharmacy and Biotechnology, Alma Mater Studiorum—University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy
Department for Life Quality Studies, Alma Mater Studiorum—University of Bologna, Corso D’Augusto 237, 47921 Rimini, Italy
Department of Chemistry ‘‘G. Ciamician’’, Alma Mater Studiorum—University of Bologna, Via Selmi 2, 40126 Bologna, Italy
Authors to whom correspondence should be addressed.
Academic Editors: Michael Decker, Diego Muñoz-Torrero and Derek J. McPhee
Received: 23 March 2016 / Revised: 27 April 2016 / Accepted: 11 May 2016 / Published: 16 May 2016
(This article belongs to the Special Issue Molecules against Alzheimer)
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Alzheimer’s disease (AD) has been defined as a multi-factorial disorder resulting from a complex array of networked cellular and molecular mechanisms. In particular, elevated levels of Aβ protein and its aggregation products in the presence of metal ions proved to be highly neurotoxic and therapeutic strategies aimed at preventing Aβ generation and oxidative stress may represent an effective approach for AD treatment. A recent paradigm for the treatment of complex diseases such as AD suggests the employment of multifunctional compounds, single chemical entities capable of simultaneously modulating different targets involved in the pathology. In this paper, the “pharmacophores combination” strategy was applied, connecting the main scaffold of the BACE-1 ligand 1 to that of the chalcone 2, as metal chelating pharmacophore, to obtain a small library of compounds. Conjugate 5 emerged as the most interesting derivative, proving to inhibit BACE-1 with low-micromolar potency, and showing neuroprotective effects. In particular, 5 proved to be able to protect from metal-associated oxidative stress by hampering intracellular Cu2+-induced ROS formation without any direct neurotoxic effect. View Full-Text
Keywords: AD; BACE-1; benzophenone; chalcone; metal chelation; natural products; Reactive oxygen species AD; BACE-1; benzophenone; chalcone; metal chelation; natural products; Reactive oxygen species

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Rampa, A.; Tarozzi, A.; Mancini, F.; Pruccoli, L.; Di Martino, R.M.C.; Gobbi, S.; Bisi, A.; De Simone, A.; Palomba, F.; Zaccheroni, N.; Belluti, F. Naturally Inspired Molecules as Multifunctional Agents for Alzheimer’s Disease Treatment. Molecules 2016, 21, 643.

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