Design and biological evaluation of multitarget compounds as potential treatment for Alzheimer disease (LB623)

Abstract

Despite of the great efforts to develop of new therapies for Alzheimer´s disease (AD) treatment, acetylcholinesterase (AChE) inhibitors are still used, being only as palliative therapeutic since the pathogenesis of AD include other factors such as amyloid beta (Aβ), free radicals, etc. For this reason, we have designed compounds that have antioxidant activity, that inhibit AChE but also beta‐secretase (BACE1) and inhibit Aβ oligomerization. These designed compounds were submitted to explore their physicochemical parameters and were submit to docking studies to evaluate their affinity on protein targets in order to select the best ligand. Results of these studies suggest that two compounds M‐1 and M‐4 were the best. These compounds were synthesized and chemically characterized. In addition, the compounds M‐1 and M‐4 were evaluated in vitro to validate the theoretical data identifying that both compounds have antioxidant activity and inhibit AChE (Ki 0.12‐0.17 μM), inhibit BACE1 (IC50 15.4 nM), also inhibits the Aβ1‐42 oligomerization. For these reasons, compound M‐1 and M‐4 represents a promising compounds to be evaluated in transgenic models of AD.