Multitarget drug design strategy: tacrine-quinone hybrids designed to block amyloid-ß aggregation and to exert anticholinesterase and antioxidant effects

We have designed, synthesized, and biologically evaluated a series of novel tacrine−naphthoquinone hybrids as anti-AD lead compounds inspired by a multitarget approach aimed to tackle AD on multiple fronts.
Nepovimova E et al., J. Med. Chem., Vol. 57 - 20, pp. 8576-8589 (2014)
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Multitarget anti-Alzheimer compounds 1-3, designed by combining a naphthoquinone function and a tacrine fragment, displayed excellent in vitro AChE (AcetylCholinEsterase) inhibitory potencies and proved to be effective as Aß (Amyloidß) anti-aggregants. The x ray analysis of 2 in complex with AChE allowed rationalizing the outstanding activity data, IC50 = 0.72nM.
The non toxic derivatives 2 and 3: (i) completely reverted the decrease in viability induced by Aß in immortalized cortical neurons; (ii) showed antioxidant activity in human glioma; and (iii) crossed the blood-brain barrier.
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Multitarget Drug Design Strategy: Quinone–Tacrine Hybrids Designed To Block Amyloid-β Aggregation and To Exert Anticholinesterase and Antioxidant Effects, Nepovimova E, Uliassi E, Korabecny J, Peña-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., Vol. 57 - 20, pp. 8576-8589 (2014);
doi: 10.1021/jm5010804
Last Updated on Monday, 08 January 2018 15:54