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

Leonardo Pisani, Roberta Farina, Marco Catto, Rosa Maria Iacobazzi, Orazio Nicolotti, Saverio Cellamare, Giuseppe Felice Mangiatordi, Nunzio Denora, Ramon Soto-Otero, Lydia Siragusa, Cosimo Damiano Altomare, Angelo Carotti

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)6791-6806
Number of pages16
JournalJournal of Medicinal Chemistry
Volume59
Issue number14
DOIs
Publication statusPublished - Jul 28 2016

ASJC Scopus subject areas

  • Medicine(all)
  • Molecular Medicine
  • Drug Discovery

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