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Insights on synthetic strategies and structure-activity relationship of donepezil and its derivatives

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Abstract

This comprehensive review focuses on the synthesis and derivatives of donepezil, a pivotal Alzheimer’s disease (AD) medication introduced in 1997. As a selective acetylcholinesterase inhibitor with 100% oral bioavailability and a 70-h half-life, donepezil’s success in neurodegenerative disorder management has spurred extensive research into its synthesis and structural modifications. The review examines diverse synthetic approaches, evaluating their efficiency, cost, toxicity, and scalability. Methods range from traditional hazardous chemicals to eco-friendly strategies. Structural modifications and their impact on biological activities are explored, emphasizing their role in developing therapeutic agents for neurodegenerative diseases. The versatility of donepezil in drug design is demonstrated through discussions on analogues and hybrids, including those with lipoic and ferulic acid. Given projections of increased AD cases, the synthesis and modification of drugs like donepezil gain paramount importance. This review consolidates information for medicinal chemists, offering insights to guide the development of efficient compounds for neurodegenerative disorder management.

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Abbreviations

AChE:

Acetylcholinesterase

AChEI:

Acetylcholinesterase inhibitor

APP:

Amyloid precursor protein

Aβ :

Amyloid beta

BACE1:

Beta-secretase 1

CA1:

Cornu ammonis

CYTA:

1-(mercaptomethyl)cyclopropane acetic acid

DCFH-DA:

Dichloro-dihydro-fluorescein diacetate

DIPEA:

N,N-diisopropylethylamine

DPPH:

2,2-diphenyl-1-picrylhydrazyl

hAChE:

Human acetylcholinesterase

HepG2:

Human liver cancer cell line

HMPA:

Hexamethylphosphoramide

HMPTA:

Hexamethylphosphoric triamide

LOX:

Leukotriene

LPS:

Lipopolysaccharide

MTDLs:

Multi-target directed ligands

MTT:

Methyl thiazolyl tetrazolium

NMR:

Nuclear magnetic resonance

PAMPA:

Parallel artificial membrane permeability assay

PAS:

Peripheral anionic site

PBMC:

Peripheral blood mononuclear cells

PyBOP:

Benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate

TEM:

Transmission Electron Microscopy

THT:

Thioflavin T

TNFα :

Tumor necrosis factor alpha

USFDA:

U.S. Food and Drug Administration

VDCC:

Voltage dependent calcium channel

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Acknowledgements

Authors are thankful to late Prof. Ina Aditya Shastri, Vice Chancellor, Banasthali Vidyapith, and Rajasthan, India for providing all necessary tools and sources for drafting this review article.

Author contributions

SP Preparation and creation of the article; SJ Editing and drawing of chemical structures; RG Data curation; SS Critical review and supervision of the manuscript; JD Editing and Supervision

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This study received no particular support from public, commercial, or non-profit funding agencies.

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  1. Department of Pharmacy, Banasthali, Vidyapith, Banasthali, Rajasthan, India

    Saraswati Patel, Ritika Gururani & Swapnil Sharma

  2. Department of Chemistry, Banasthali, Vidyapith, Banasthali, Rajasthan, India

    Sonika Jain & Jaya Dwivedi

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  1. Saraswati Patel
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Patel, S., Jain, S., Gururani, R. et al. Insights on synthetic strategies and structure-activity relationship of donepezil and its derivatives. Med Chem Res 33, 370–405 (2024). https://doi.org/10.1007/s00044-024-03186-3

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  • DOI: https://doi.org/10.1007/s00044-024-03186-3

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