SYNTHESIS, PHARMACOLOGICAL EVALUATION, AND MOLECULAR MODELING OF A NOVEL FAMILY OF 6-CHLOROTACRINE-BASED DUAL BINDING SITE ACETYLCHOLINESTERASE INHIBITORS

In the last decade, the design of novel classes of inhibitors of the enzyme acetylcholinesterase (AChE) as therapeutic interventions for Alzheimer’s disease (AD) has been mostly driven by the pivotal finding that AChE can bind the β-amyloid peptide (Aβ), thereby promoting Aβ aggregation as an early event in the neurodegenerative cascade of AD. Blockade of the peripheral site of AChE, the Aβ recognition zone within the enzyme, is expected to affect the AChE-induced Aβ aggregation and could be a potential strategy to modulate the progression of AD. Novel classes of AChE inhibitors (AChEIs) targeting the peripheral site of AChE are emerging as promising disease-modifying anti-Alzheimer drug candidates. Of particular interest are the so-called dual binding site AChEIs, i.e. inhibitors able to simultaneously bind both the active and peripheral sites of AChE, which exhibit significant Aβ antiaggregating effects and high AChE inhibitory potencies. Two isomeric series of dual binding site AChEIs have been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase, AChE-induced and self-induced Aβ aggregation and β-secretase (BACE-1). The new hybrids consist of a unit of 6-chlorotacrine and a multicomponent reactionderived pyrano[3,2-c]quinoline scaffold as the active-site and peripheral-site interacting moieties, respectively, connected through an oligomethylene linker containing an amido group at variable position. Molecular modeling studies have confirmed the dual site binding of these hybrids, which retain the potent and selective human AChE inhibitory activity of the parent 6-chlorotacrine, while exhibiting a significant in vitro Aβ anti-aggregating effect and BACE-1 inhibitory activity, thus constituting promising anti-Alzheimerdrug candidates.