Dual Inhibitors of beta-Amyloid Aggregation and Acetylcholinesterase as Multi-Target Anti-Alzheimer Drug Candidates

Notwithstanding the functional role that the aggregates of some amyloidogenic proteins can play in different organisms, protein aggregation plays a pivotal role in the pathogenesis of a large number of human diseases. One of such diseases is Alzheimer's disease (AD), where the overproduction and aggregation of the beta-amyloid peptide (A beta) are regarded as early critical factors. Another protein that seems to occupy a prominent position within the complex pathological network of AD is the enzyme acetylcholinesterase (AChE), with classical and non-classical activities involved at the late (cholinergic deficit) and early (A beta aggregation) phases of the disease. Dual inhibitors of A beta aggregation and AChE are thus emerging as promising multi-target agents with potential to efficiently modify the natural course of AD. In the initial phases of the drug discovery process of such compounds, in vitro evaluation of the inhibition of A beta aggregation is rather troublesome, as it is very sensitive to experimental assay conditions, and requires expensive synthetic A beta peptides, which makes cost-prohibitive the screening of large compound libraries. Herein, we review recently developed multi-target anti-Alzheimer compounds that exhibit both A beta aggregation and AChE inhibitory activities, and, in some cases also additional valuable activities such as BACE-1 inhibition or antioxidant properties. We also discuss the development of simplified in vivo methods for the rapid, simple, reliable, unexpensive, and high-throughput amenable screening of A beta aggregation inhibitors that rely on the overexpression of A beta 42 alone or fused with reporter proteins in Escherichia coli.