Multidirectional <i>in vitro</i> and <i>in cellulo</i> studies as a tool for identification of multi-target-directed ligands aiming at symptoms and causes of Alzheimer’s disease

Abstract

Effective therapy of Alzheimer's disease (AD) requires treatment with a combination of drugs that modulate various pathomechanisms contributing to the disease. In our research, we have focused on the development of multi-target-directed ligands - 5-HT₆ receptor antagonists and cholinesterase inhibitors - with disease-modifying properties. We have performed extended <i>in vitro</i> (FRET assay) and <i>in cellulo</i> (<i>Escherichia coli</i> model of protein aggregation) studies on their β-secretase, tau, and amyloid β aggregation inhibitory activity. Within these multifunctional ligands, we have identified compound <b>17</b> with inhibitory potency against tau and amyloid β aggregation in <i>in cellulo</i> assay of 59% and 56% at 10 µM, respectively, <i>h</i>BACE IC₅₀=4 µM, <i>h</i>5TH6 <i>K</i> _i=94 nM, <i>h</i>AChE IC₅₀=26 nM, and <i>eq</i>BuChE IC₅₀=5 nM. This study led to the development of multifunctional ligands with a broad range of biological activities crucial not only for the symptomatic but also for the disease-modifying treatment of AD.