A novel hybrid of 6-chlorotacrine and metal-amyloid-beta modulator for inhibition of acetylcholinesterase and metal-induced amyloid-beta aggregation

The number of people suffering from Alzheimer's disease (AD) is expected to increase dramatically in the coming decades. Currently, acetylcholinesterase inhibitors (AChEis) provide some relief of cognitive symptoms, while newer approaches, such as amyloid-beta (A beta)-targeted metal chelation, offer potential hope for slowing and/or reversing disease progression. This work details the synthesis and biochemical evaluation of a novel hybrid of 6-chlorotacrine and a metal-A beta modulator that chemically combines an AChEi and an A beta-targeted metal chelator into a single molecule. This hybrid shows potent inhibition of AChE under various conditions, interaction with Cu2+ and Zn2+, control of metal-free and metal-induced A beta aggregate assembly, and disaggregation of preformed metal-free and metal-associated A beta aggregates. As such, the hybrid described herein represents a promising, new multifunctional compound for AD studies.