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Lead optimization based design, synthesis, and pharmacological evaluation of quinazoline derivatives as multi-targeting agents for Alzheimer's disease treatment.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2024 May 05; Vol. 271, pp. 116450. Date of Electronic Publication: 2024 Apr 27. - Publication Year :
- 2024
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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.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Animals
Humans
Rats
Structure-Activity Relationship
Molecular Structure
Neuroprotective Agents pharmacology
Neuroprotective Agents chemical synthesis
Neuroprotective Agents chemistry
Dose-Response Relationship, Drug
Butyrylcholinesterase metabolism
Male
Quinazolines pharmacology
Quinazolines chemical synthesis
Quinazolines chemistry
Alzheimer Disease drug therapy
Alzheimer Disease metabolism
Drug Design
Cholinesterase Inhibitors pharmacology
Cholinesterase Inhibitors chemical synthesis
Cholinesterase Inhibitors chemistry
Acetylcholinesterase metabolism
Amyloid beta-Peptides metabolism
Amyloid beta-Peptides antagonists & inhibitors
Amyloid Precursor Protein Secretases antagonists & inhibitors
Amyloid Precursor Protein Secretases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 271
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38701714
- Full Text :
- https://doi.org/10.1016/j.ejmech.2024.116450