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Publication Abstract from PubMed

We report the identification of multitarget anti-Alzheimer compounds designed by combining a naphthoquinone function and a tacrine fragment. In vitro, 12-29 displayed excellent acetylcholinesterase (AChE) inhibitory potencies and interesting capabilities to block amyloid-beta (Abeta) aggregation. The X-ray analysis of AChE-20 complex allowed rationalizing the outstanding activity data (IC50 = 0.72 nM). Selected compounds 16 and 20 showed negligible toxicity in immortalized mouse cortical neurons Neuro2A and primary rat cerebellar granule neurons. However, only 16 was less hepatotoxic than tacrine in HepG2 cells. In T67 cells, 16 and 20 showed antioxidant activity, following NQO1 induction. Furthermore in Neuro2A, they were able to completely revert the decrease in viability induced by Abeta. Importantly, they crossed the blood-brain barrier, as demonstrated in ex vivo experiments with rats. When ex vivo results were combined with in vitro studies, 16 and 20 emerged to be promising multitarget lead candidates worthy of further pursuit.

Multitarget drug design strategy: quinone-tacrine hybrids designed to block amyloid-beta aggregation and to exert anticholinesterase and antioxidant effects.,Nepovimova E, Uliassi E, Korabecny J, Pena-Altamira LE, Samez S, Pesaresi A, Garcia GE, Bartolini M, Andrisano V, Bergamini C, Fato R, Lamba D, Roberti M, Kuca K, Monti B, Bolognesi ML J Med Chem. 2014 Sep 26. PMID:25259726^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.