2. Academic Validation
  3. In vitro and in vivo Investigations of 4-Substituted 2-Phenylquinazoline derivatives as multipotent ligands for the treatment of Alzheimer's disease

In vitro and in vivo Investigations of 4-Substituted 2-Phenylquinazoline derivatives as multipotent ligands for the treatment of Alzheimer's disease

  • Bioorg Chem. 2025 Feb:155:108126. doi: 10.1016/j.bioorg.2025.108126.
Vijay Kumar 1,  Kailash Jangid 1,  Vishal Kumar 2,  Naveen Kumar 1,  Jayapriya Mishra 3,  Tania Arora 4,  Ashish Ranjan Dwivedi 5,  Puneet Kumar 2,  Jasvinder Singh Bhatti 3,  Jyoti Parkash 4,  Vinod Kumar 6
Affiliations

Affiliations

  • 1 Laboratory of Organic and Medicinal Chemistry, Department of Chemistry, Central University of Punjab, Bathinda, India, 151401.
  • 2 Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, Punjab, India, 151401.
  • 3 Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, Central University of Punjab, Ghudda, Bathinda, Punjab, India, 151401.
  • 4 Neurochemistry and Neuroendocrinology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India, 151401.
  • 5 Laboratory of Organic and Medicinal Chemistry, Department of Chemistry, Central University of Punjab, Bathinda, India, 151401; Gitam School of Pharmacy, Hyderabad, Telangana, 502329, India.
  • 6 Laboratory of Organic and Medicinal Chemistry, Department of Chemistry, Central University of Punjab, Bathinda, India, 151401. Electronic address: vinod.kumar@cup.edu.in.
PMID: 39798452 DOI: 10.1016/j.bioorg.2025.108126
Abstract

The pathology of Alzheimer's disease (AD) is complex due to its multifactorial nature and single targeting drugs proved inefficient. A series of novel 4-N-substituted-2-phenylquinazoline derivatives was designed and synthesized as potential multi-target directed ligands (MTDLs) through dual inhibition of AChE and MAO-B Enzymes along with Aβ42 aggregation inhibition for the treatment of AD. Two compounds in the series, VAV-8 and VAV-19 were found to be the most potent inhibitors of both AChE and MAO-B Enzymes and moderate inhibitor of Aβ42, with good thermodynamic stability at the binding pocket of the Enzymes. Both the ligands showed moderate ROS inhibition and neuroprotection potential and found to be permeable to the blood-brain barrier. Furthermore, VAV-8 was subjected to toxicity evaluation and in vivo investigation using a zebrafish model. In adult zebrafish, VAV-8 (5 μM, and 10 μM) was found to be effective in reducing cognitive deterioration, neurodegeneration, and oxidative stress induced by scopolamine. Thus, these quinazoline derivatives have the potential to be developed as MTDLs for the treatment of Alzheimer's disease.

Keywords

2-Phenylquinazoline derivatives; Acetylcholine esterase inhibitors; Alzheimer’s disease; Aβ(42) aggregation inhibitors; Monoamine oxidase inhibitors; Multi-Target Directed Ligands.

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