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Alzheimer’s disease (AD) is the most common form of dementia affecting more than 28 million people in the world. Only symptomatic treatments are currently available. Anticipated tri-fold increase of AD incidence in the next 50 years has established the need to explore new possible treatments. Accumulation of extracellular amyloid-b (Ab) plaques, intracellular tangles in the brain, and formation of reactive oxygen species (ROS) are the major hallmarks of the disease. The active role of some metal ions, especially Cu2+, in promoting both Ab aggregation and reactive oxygen species formation has rendered ionophoric drugs as a promising treatment strategy. In this work, a series of 5 disease-modifying and multi-target ionophoric polyphenols (1-5), inspired on the structure of natural resveratrol, have been synthesized and characterized. All compounds bind Cu2+ selectively over other biologically relevant metal ions. They form 2:1 (compound:Cu2+) complexes with association constants logKa 12-14 depending on the molecular design. Our results indicate that compounds 1-5 possess excellent antioxidant properties: they inhibit the Cu2+-catalyzed reactive oxygen species production between 47% and 100%, and they scavenge DPPH (1,1-diphenyl-2-picryl-hydrazyl) and AAPH (2,2’-azobis(2-amindino-propane) dihydrochloride) free radicals in general better than clioquinol, resveratrol and ascorbic acid. In addition, compounds 1-5 interact with Ab peptides and inhibit both the Cu2+-catalyzed aggregation and the self-assembly of Ab(1-40) up to a ~92% extent. Interestingly, 1-5 are also able to disaggregate up to ~91% of pre-formed Ab(1-40) aggregates. Furthermore, cytotoxic studies show remarkably low toxicity of 1-5 toward Tetrahymena thermophila with LD50 values higher than 150 mM, comparable to non-toxic natural resveratrol.



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