Multi-Target-Directed Ligands in Alzheimer's Disease Treatment

Alzheimer's disease (AD) is a complex neurodegenerative disorder arising from multiple molecular abnormalities including a progressive forebrain cholinergic deficiency, accumulation of misfolded protein deposits as amyloid ? plaques and a redox system impairment which lead to increased levels of reactive oxygen species and to the consequent radicals mediated injury. To date, the only licensed AD treatments are acetylcholinesterase (AChE) inhibitors and memantine, which are valuable in restoring cholinergic deficit but offer only a modest and temporary benefits to patients[1] . In the fight of AD recently has been proposed a move from the classic "one protein, one target, one drug" strategy to a strategy of developing drugs that simultaneously target multiple targets [2]. We report on the structure-activity relationships of two novel multitarget anti-Alzheimer compounds designed by combining a tacrine fragment and a juglone [3] or benzofuran moiety respectively, with a linker of a suitable length. In vitro, both compounds displayed excellent AChE inhibitory potencies and interesting capabilities to block amyloid-? aggregation and anti-oxidants properties. The X-ray analysis of the Torpedo californica AChE - inhibitor complexes allowed a structure-based rationale for the outstanding activity data. [1] M. Rosini, E. Simoni, A. Minarini, C. Melchiorre Neurochem. Res. 2014, 39, 1914. [2] A. Cavalli, M.L. Bolognesi, A. Minarini, M. Rosini, V. Tumiatti, M. Recanatini, C. Melchiorre J. Med. Chem. 2008, 51,347. [3] E. Nepovimova, E. Uliassi, J. Korabecny, L.E. Peña-Altamira, S. Samez, A. Pesaresi, G.E. Garcia, M. Bartolini, M. Andrisano, C. Bergamini, R. Fato, D. Lamba, M. Roberti, K. Kuca, B. Monti, M.L. Bolognesi J. Med. Chem. 2014, 57, 8576.