Exploring Basic Tail Modifications of Coumarin-Based Dual Acetylcholinesterase-Monoamine Oxidase B Inhibitors: Identification of Water-Soluble, Brain-Permeant Neuroprotective Multitarget Agents

Aiming
at modulating two key enzymatic targets for Alzheimer’s
disease (AD), i.e., acetylcholinesterase (AChE) and monoamine oxidase
B (MAO B), a series of multitarget ligands was properly designed by
linking the 3,4-dimethylcoumarin scaffold to 1,3- and 1,4-substituted
piperidine moieties, thus modulating the basicity to improve the hydrophilic/lipophilic
balance. After in vitro enzymatic inhibition assays, multipotent inhibitors
showing potencies in the nanomolar and in the low micromolar range
for hMAO B and eeAChE, respectively, were prioritized and evaluated
in human SH-SY5Y cell-based models for their cytotoxicity and neuroprotective
effect against oxidative toxins (H2O2, rotenone,
and oligomycin-A). The present study led to the identification of
a promising multitarget hit compound (5b) exhibiting
high hMAO B inhibitory activity (IC50 = 30 nM) and good
MAO B/A selectivity (selectivity index, SI = 94) along with a micromolar
eeAChE inhibition (IC50 = 1.03 μM). Moreover, 5b behaves as a water-soluble, brain-permeant neuroprotective
agent against oxidative insults without interacting with P-gp efflux
system.