Lead optimization based design, synthesis, and pharmacological evaluation of quinazoline derivatives as multi-targeting agents for Alzheimer's disease treatment

Eur J Med Chem. 2024 May 5:271:116450. doi: 10.1016/j.ejmech.2024.116450. Epub 2024 Apr 27.

Abstract

The complexity and multifaceted nature of Alzheimer's disease (AD) have driven us to further explore quinazoline scaffolds as multi-targeting agents for AD treatment. The lead optimization strategy was utilized in designing of new series of derivatives (AK-1 to AK-14) followed by synthesis, characterization, and pharmacological evaluation against human cholinesterase's (hChE) and β-secretase (hBACE-1) enzymes. Amongst them, compounds AK-1, AK-2, and AK-3 showed good and significant inhibitory activity against both hAChE and hBACE-1 enzymes with favorable permeation across the blood-brain barrier. The most active compound AK-2 revealed significant propidium iodide (PI) displacement from the AChE-PAS region and was non-neurotoxic against SH-SY5Y cell lines. The lead molecule (AK-2) also showed Aβ aggregation inhibition in a self- and AChE-induced Aβ aggregation, Thioflavin-T assay. Further, compound AK-2 significantly ameliorated Aβ-induced cognitive deficits in the Aβ-induced Morris water maze rat model and demonstrated a significant rescue in eye phenotype in the Aꞵ-phenotypic drosophila model of AD. Ex-vivo immunohistochemistry (IHC) analysis on hippocampal rat brains showed reduced Aβ and BACE-1 protein levels. Compound AK-2 suggested good oral absorption via pharmacokinetic studies and displayed a good and stable ligand-protein interaction in in-silico molecular modeling analysis. Thus, the compound AK-2 can be regarded as a lead molecule and should be investigated further for the treatment of AD.

Keywords: Acetylcholinesterase; Alzheimer's disease; Amyloid-β; In-vivo studies; Multi-targeting agents; Quinazoline; β-secretase-1.

MeSH terms

  • Acetylcholinesterase* / metabolism
  • Alzheimer Disease* / drug therapy
  • Alzheimer Disease* / metabolism
  • Amyloid Precursor Protein Secretases* / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases* / metabolism
  • Amyloid beta-Peptides* / antagonists & inhibitors
  • Amyloid beta-Peptides* / metabolism
  • Animals
  • Butyrylcholinesterase / metabolism
  • Cholinesterase Inhibitors* / chemical synthesis
  • Cholinesterase Inhibitors* / chemistry
  • Cholinesterase Inhibitors* / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Male
  • Molecular Structure
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology
  • Quinazolines* / chemical synthesis
  • Quinazolines* / chemistry
  • Quinazolines* / pharmacology
  • Rats
  • Structure-Activity Relationship

Substances

  • Quinazolines
  • Cholinesterase Inhibitors
  • Acetylcholinesterase
  • Amyloid beta-Peptides
  • Amyloid Precursor Protein Secretases
  • Neuroprotective Agents
  • Butyrylcholinesterase