Synthesis, biological evaluation, and molecular modeling of nitrile-containing compounds: Exploring multiple activities as anti-Alzheimer agents

Daniel Silva, Eduarda Mendes, Eleanor J. Summers, Ana Neca, Ana C. Jacinto, Telma Reis, Paula Agostinho, Irene Bolea, M. Luisa Jimeno, M. Luisa Mateus, Ana M.F. Oliveira-Campos, Mercedes Unzeta, José Marco-Contelles, Magdalena Majekova, Rona R. Ramsay, M. Carmo Carreiras

Research output: Contribution to journalArticleResearch

3 Citations (Scopus)

Abstract

Based on the monoamine oxidase (MAO) inhibition properties of aminoheterocycles with a carbonitrile group we have carried out a systematic exploration to discover new classes of carbonitriles endowed with dual MAO and AChE inhibitory activities, and A beta anti-aggregating properties. Eighty-three nitrile-containing compounds, 13 of which are new, were synthesized and evaluated. in vitro screening revealed that 31, a new compound, presented the best lead for trifunctional inhibition against MAO A (0.34 mu M), MAO B (0.26 mu M), and AChE (52 mu M), while 32 exhibited a lead for selective MAO A (0.12 mu M) inhibition coupled to AChE (48 mu M) inhibition. Computational analysis revealed that the malononitrile group can find an advantageous position with the aromatic cleft and FAD of MAO A or MAO B. However, the total binding energy can be handicapped by an internal penalty caused by twisting of the ligand molecule and subsequent disruption of the conjugation (32 in MAO B compared to the conjugated 31). Conjugation is also important for AChE as well as the hydrophilic character of malononitrile that allows this group to be in close contact with the aqueous environment as seen for 83. Although the effect of 31 and 32 against A beta(1-42), was very weak, the effect of 63 and 65, and of the new compound 75, indicated that these compounds were able to disaggregate A beta(1-42) fibrils. The most effective was 63, a (phenylhydrazinylidene)propanedinitrile derivative that also inhibited MAO A (1.65 mu M), making it a potential lead for Alzheimer's disease application.

Original languageEnglish
Number of pages17
JournalDrug Development Research
DOIs
Publication statusPublished - 30 Aug 2019

Keywords

  • A beta(1-42) disaggregating agents
  • ACETYLCHOLINESTERASE
  • AChE inhibitors
  • Alzheimer's disease
  • BETA-PEPTIDE
  • DISEASE
  • DUAL ACHE INHIBITORS
  • HUMAN URINE
  • MAJOR METABOLITES
  • MAO inhibitors
  • MONOAMINE-OXIDASE
  • PHARMACOLOGICAL ASSESSMENT
  • POTENTIAL-DRUGS
  • SELECTIVE-INHIBITION
  • in silico study
  • nitrile-containing compounds

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