New flavonoid - N, N-dibenzyl(N-methyl)amine hybrids: Multi-target-directed agents for Alzheimer´s disease endowed with neurogenic properties

J Enzyme Inhib Med Chem. 2019 Dec;34(1):712-727. doi: 10.1080/14756366.2019.1581184.

Abstract

The design of multi-target directed ligands (MTDLs) is a valid approach for obtaining effective drugs for complex pathologies. MTDLs that combine neuro-repair properties and block the first steps of neurotoxic cascades could be the so long wanted remedies to treat neurodegenerative diseases (NDs). By linking two privileged scaffolds with well-known activities in ND-targets, the flavonoid and the N,N-dibenzyl(N-methyl)amine (DBMA) fragments, new CNS-permeable flavonoid - DBMA hybrids (1-13) were obtained. They were subjected to biological evaluation in a battery of targets involved in Alzheimer's disease (AD) and other NDs, namely human cholinesterases (hAChE/hBuChE), β-secretase (hBACE-1), monoamine oxidases (hMAO-A/B), lipoxygenase-5 (hLOX-5) and sigma receptors (σ1R/σ2R). After a funnel-type screening, 6,7-dimethoxychromone - DBMA (6) was highlighted due to its neurogenic properties and an interesting MTD-profile in hAChE, hLOX-5, hBACE-1 and σ1R. Molecular dynamic simulations showed the most relevant drug-protein interactions of hybrid 6, which could synergistically contribute to neuronal regeneration and block neurodegeneration.

Keywords: Alzheimer’s disease; Multi-target-directed ligands; human cholinesterases; human lipoxygenase-5; human β-secretase; neurodegenerative diseases; neurogenesis; sigma receptors.

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases / metabolism
  • Animals
  • Arachidonate 5-Lipoxygenase / metabolism
  • Aspartic Acid Endopeptidases / antagonists & inhibitors
  • Aspartic Acid Endopeptidases / metabolism
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism
  • Butyrylcholinesterase / metabolism
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Flavonoids / chemistry
  • Flavonoids / pharmacology*
  • Humans
  • Male
  • Methylamines / chemistry
  • Methylamines / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Molecular
  • Molecular Structure
  • Monoamine Oxidase / metabolism
  • Nerve Regeneration / drug effects*
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*

Substances

  • Enzyme Inhibitors
  • Flavonoids
  • Methylamines
  • Neuroprotective Agents
  • Arachidonate 5-Lipoxygenase
  • ALOX5 protein, human
  • Monoamine Oxidase
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human

Grants and funding

The authors gratefully acknowledge the following financial supports: Spanish Ministry of Science, Innovation and Universities (grants SAF2015-64948-C2-1-R and RTI2018-093955-B-C21 to MIRF; grant SAF2017-85199-P to APC), Spanish National Research Council (CSIC, grant PIE-201580E109 to MIRF), General Council for Research and Innovation of the Community of Madrid and European Structural Funds (grant B2017/BMD-3827 – NRF24AD-CM to MIRF), Consellería de Cultura, Educación e Ordenación Universitaria de Galicia, and the European Regional Development Fund (ERDF) (accreditation 2016–2019, ED431G/05 to DV). EL and SP gratefully acknowledge the support of NVIDIA Corporation with the donation of the Titan Xp GPU used for this research. MEV and CH-A also thank their PhD fellowships from Departamento Administrativo de Ciencia, Tecnología e Innovación (COLCIENCIAS, Colombia) and Spanish Ministry of Education (MEC, grant FPU16/01704), respectively. JAM-G is a fellow from the Biomedical Research Networking Centre on Neurodegenerative Diseases (CIBERNED, Spain).