New benzyl pyridinium derivatives bearing 2,4-dioxochroman moiety as potent agents for treatment of Alzheimer's disease: Design, synthesis, biological evaluation, and docking study

Marjan Mollazadeh; Maryam Mohammadi-Khanaposhtani; Afsaneh Zonouzi; Hamid Nadri; Zahra Najafi; Bagher Larijani; Mohammad Mahdavi

doi:10.1016/j.bioorg.2019.03.012

New benzyl pyridinium derivatives bearing 2,4-dioxochroman moiety as potent agents for treatment of Alzheimer's disease: Design, synthesis, biological evaluation, and docking study

Bioorg Chem. 2019 Jun:87:506-515. doi: 10.1016/j.bioorg.2019.03.012. Epub 2019 Mar 6.

Authors

Marjan Mollazadeh¹, Maryam Mohammadi-Khanaposhtani², Afsaneh Zonouzi³, Hamid Nadri⁴, Zahra Najafi⁵, Bagher Larijani⁶, Mohammad Mahdavi⁷

Affiliations

¹ School of Chemistry, College of Science, University of Tehran, Tehran, Iran.
² Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
³ School of Chemistry, College of Science, University of Tehran, Tehran, Iran. Electronic address: zonouzi@khayam.ut.ac.ir.
⁴ Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
⁵ Department of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran; Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran.
⁶ Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
⁷ Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: momahdavi@tums.ac.ir.

PMID: 30928873
DOI: 10.1016/j.bioorg.2019.03.012

Abstract

A new series of benzyl pyridinium-2,4-dioxochroman derivatives 7a-o was synthesized and evaluated as new anti-Alzheimer agents. Among the synthesized compounds, the compounds 7f and 7i exhibited the most potent anti-AChE and anti-BuChE activities, respectively. The kinetic study of the compound 7f revealed that this compound inhibited AChE in a mixed-type inhibition mode. Furthermore, the docking study of the compounds 7f and 7i showed that these compounds bound to both the catalytic site (CS) and peripheral anionic site (PAS) of AChE and BuChE, respectively. The compound 7f also exhibited a greater self-induced Aβ peptide aggregation inhibitory activity in compare to donepezil. Furthermore, the neuroprotective activity of this compound at 20 μM was comparable to that of the standard neuroprotective agent (quercetin).

Keywords: 2,4-Dioxochroman; Acetylcholinesterase; Alzheimer’s disease; Benzyl pyridinium; Butyrylcholinesterase; Docking study.

MeSH terms

Acetylcholinesterase / metabolism
Alzheimer Disease / drug therapy*
Alzheimer Disease / metabolism
Amyloid beta-Peptides / antagonists & inhibitors
Amyloid beta-Peptides / metabolism
Animals
Benzyl Compounds / chemical synthesis
Benzyl Compounds / chemistry
Benzyl Compounds / pharmacology*
Butyrylcholinesterase / metabolism
Cell Death / drug effects
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Chromans / chemistry
Chromans / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Humans
Hydrogen Peroxide / antagonists & inhibitors
Hydrogen Peroxide / pharmacology
Molecular Docking Simulation
Molecular Structure
Neuroprotective Agents / chemical synthesis
Neuroprotective Agents / chemistry
Neuroprotective Agents / pharmacology*
PC12 Cells
Pyridinium Compounds / chemical synthesis
Pyridinium Compounds / chemistry
Pyridinium Compounds / pharmacology*
Rats
Structure-Activity Relationship

Substances

Amyloid beta-Peptides
Benzyl Compounds
Cholinesterase Inhibitors
Chromans
Neuroprotective Agents
Pyridinium Compounds
Hydrogen Peroxide
Acetylcholinesterase
Butyrylcholinesterase