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  2. Synthesis of novel aryl-substituted 2-aminopyridine derivatives by the cascade reaction of 1,1-enediamines with vinamidinium salts to develop novel anti-Alzheimer agents

Synthesis of novel aryl-substituted 2-aminopyridine derivatives by the cascade reaction of 1,1-enediamines with vinamidinium salts to develop novel anti-Alzheimer agents

  • Sci Rep. 2024 Jun 14;14(1):13780. doi: 10.1038/s41598-024-64179-1.
Sama Loori 1 Hormoz Pourtaher 1 Abdolmohammad Mehranpour 2 Alireza Hasaninejad 1 Mohammadreza Eftekharian 3 Aida Iraji 4 5
Affiliations

Affiliations

  • 1 Department of Chemistry, Faculty of Sciences, Persian Gulf University, Bushehr, 75169, Iran.
  • 2 Department of Chemistry, Faculty of Sciences, Persian Gulf University, Bushehr, 75169, Iran. ammehranpour@hotmail.com.
  • 3 Student Research Committee, Jahrom University of Medical Sciences, Jahrom, Iran.
  • 4 Department of Persian Medicine, School of Medicine, Research Center for Traditional Medicine and History of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran. iraji@sums.ac.ir.
  • 5 Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. iraji@sums.ac.ir.
Abstract

Alzheimer's disease (AD), a severe neurodegenerative disorder, imposes socioeconomic burdens and necessitates innovative therapeutic strategies. Current therapeutic interventions are limited and underscore the need for novel inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), Enzymes implicated in the pathogenesis of AD. In this study, we report a novel synthetic strategy for the generation of 2-aminopyridine derivatives via a two-component reaction converging aryl vinamidinium salts with 1,1-enediamines (EDAMs) in a dimethyl sulfoxide (DMSO) solvent system, catalyzed by triethylamine (Et3N). The protocol introduces a rapid, efficient, and scalable synthetic pathway, achieving good to excellent yields while maintaining simplistic workup procedures. Seventeen derivatives were synthesized and subsequently screened for their inhibitory activity against AChE and BChE. The most potent derivative, 3m, exhibited an IC50 value of 34.81 ± 3.71 µM against AChE and 20.66 ± 1.01 µM against BChE compared to positive control donepezil with an IC50 value of 0.079 ± 0.05 µM against AChE and 10.6 ± 2.1 µM against BChE. Also, detailed kinetic studies were undertaken to elucidate their modes of enzymatic inhibition of the most potent compounds against both AChE and BChE. The promising compound was then subjected to molecular docking and dynamics simulations, revealing significant binding affinities and favorable interaction profiles against AChE and BChE. The in silico ADMET assessments further determined the drug-like properties of 3m, suggesting it as a promising candidate for further pre-clinical development.

Keywords

1,1-Enediamines; Alzheimer; Aryl vinamidinium salts; Aryl-substituted 2-aminopyridine; Molecular dynamic simulation.

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