Investigating alkyl nitrates as nitric oxide releasing precursors of multitarget acetylcholinesterase-monoamine oxidase B inhibitors

Leonardo Pisani, Rosa Maria Iacobazzi, Marco Catto, Mariagrazia Rullo, Roberta Farina, Nunzio Denora, Saverio Cellamare, Cosimo Damiano Altomare

Research output: Contribution to journalArticlepeer-review

Abstract

Herein we envisaged the possibility of exploiting alkyl nitrates as precursors of alcohol-bearing dual inhibitors targeting acetylcholinesterase (AChE) and monoamine oxidase B (MAO B), key enzymes in neurodegenerative syndromes such as Alzheimer's disease (AD), through biotransformation unmasking an alcoholic function upon nitric oxide (NO) release. The cooperation to neuroprotection of low fluxes of NO and target enzymes’ inhibition by the alcohol metabolites might return a multitargeting effect. The in vitro screening towards ChEs and MAOs of a collection of 21 primary alcohols disclosed a subset of dual inhibitors, among which three diverse chemotypes were selected to study the corresponding nitrates. Nitrate 14 proved to be a brain permeant, potent AChE-MAO B inhibitor by itself. Moreover, it protected human SH-SY5Y lines against rotenone and hydrogen peroxide with a poor inherent cytotoxicity and showed a slow conversion profile to its alcohol metabolite 9d that still behaved as bimodal and neuroprotective molecule.

Original languageEnglish
Pages (from-to)292-309
Number of pages18
JournalEuropean Journal of Medicinal Chemistry
Volume161
DOIs
Publication statusPublished - Jan 1 2019

Keywords

  • Acetylcholinesterase
  • Monoamine oxidase B
  • Multitargeting agents
  • Nitric oxide donor

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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