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

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 Abeta (Amyloidbeta) 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.