Design, synthesis, and evaluation of novel O-alkyl ferulamide derivatives as multifunctional ligands for treating Alzheimer's disease

J Enzyme Inhib Med Chem. 2022 Dec;37(1):1375-1388. doi: 10.1080/14756366.2022.2073442.

Abstract

Herein, a series of novel O-alkyl ferulamide derivatives were designed and synthesised through the multi-target-directed ligands (MTDLs) strategy. The biological activities in vitro showed that compounds 5a, 5d, 5e, 5f, and 5h indicated significantly selective MAO-B inhibitory potency (IC50 = 0.32, 0.56, 0.54, 0.73, and 0.86 μM, respectively) and moderate antioxidant activity. Moreover, compounds 5a, 5d, 5e, 5f, and 5h showed potent anti-inflammatory properties, remarkable effects on self-induced Aβ1-42 aggregation, and potent neuroprotective effect on Aβ1-42-induced PC12 cell injury. Furthermore, compounds 5a, 5d, 5e, 5f, and 5h presented good blood-brain barrier permeation in vitro and drug-like properties. More interesting, the PET/CT images with [11C]5f demonstrated that [11C]5f could penetrate the BBB with a high brain uptake and exhibited good brain clearance kinetic property. Therefore, compound 5f would be a promising multi-functional agent for the treatment of AD.

Keywords: Alzheimer’s disease; O-alkyl ferulamide derivatives; PET-CT imaging; multifunctional agents.

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease* / drug therapy
  • Amyloid beta-Peptides
  • Cholinesterase Inhibitors / pharmacology
  • Drug Design
  • Humans
  • Ligands
  • Molecular Structure
  • Neuroprotective Agents*
  • Positron Emission Tomography Computed Tomography
  • Protein Aggregates
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Cholinesterase Inhibitors
  • Ligands
  • Neuroprotective Agents
  • Protein Aggregates
  • Acetylcholinesterase

Grants and funding

This work was financially supported by the National-Local Joint Engineering Research Center for Innovative & Generic Chemical Drug, and Guizhou High-level Innovative Talents Supporting Program (2016–4015); The State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University (Grant number FAMP202107K); Guizhou Science and Technology Platform Talents (QKHRCPT[2019]5627), and the Special Project of Nanyang Normal University (2022QN003).