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Synthesis of novel 4-methylthiocoumarin and comparison with conventional coumarin derivative as a multi-target-directed ligand in Alzheimer’s disease

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Abstract

Alzheimer’s disease (AD) is a multifactorial disorder characterized by cognitive deficit and memory loss. The pathological feature of the disease involves β-amyloid senile plaques, reduced levels of acetylcholine neurotransmitter, oxidative stress and neurofibrillary tangles formation within the brain of AD patients. The present study aims to screen the inhibitory activity of newly synthesized and existing novel 4-methylthiocoumarin derivative against acetylcholinesterase, butyrylcholinesterase, BACE1, β-amyloid aggregation and oxidative stress involved in the AD pathogenesis. The in vitro assays used in this study were Ellman’s assay, FRET assays, Thioflavin T, transmission electron microscopy, circular dichroism, FRAP, and TEAC. Molecular docking and dynamics studies were performed to correlate the results. C3 and C7 (thiocoumarin derivatives) were found to be the most potent inhibitors of acetylcholinesterase (IC50-5.63 µM) and butyrylcholinesterase (IC50-3.40 µM) using Ellman’s assays. Enzyme kinetic studies showed that C3 and C7 compounds followed by the mixed mode of inhibition using LB plot. C3 also moderately inhibited the BACE1 using FRET assay. C3 inhibited the fibrillization of β-amyloid peptides in a concentration-dependent manner as observed by Thioflavin T, TEM studies and Circular dichroism data. Molecular modeling studies were performed to understand the probable mode of binding of C3 and C7 in the binding pocket of acetylcholinesterase, butyrylcholinesterase, BACE1 and amyloid β peptides. This indicates the important role of hydrophobic interactions between C3 and acetylcholinesterase. C3 also exhibited significant antioxidant potential by FRAP and TEAC assays. Hence, C3 might serve as a promising lead for developing novel multi target-directed ligand for the treatment of AD.

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Abbreviations

AD:

Alzheimer’s disease

CNS:

Central nervous system

Aβ:

Amyloid β

MTDLs:

Multi-target-directed ligands

BACE1:

β-Secretase cleavage enzyme

MAO B:

Monoamine oxidase B

AChE:

Acetylcholinesterase

BuChE:

Butyrylcholinesterase

Ach:

Acetylcholine

APP:

Amyloid precursor protein

ROS:

Reactive oxygen species

FAD:

Flavin adenine dinucleotide

H2O2 :

Hydrogen peroxide

AChEI:

AChE inhibitor

TEM:

Transmission electron microscope

CD:

Circular dichroism

donorHB:

Hydrogen bond donor

accptHB:

Hydrogen bond acceptor

BBB:

Blood–brain barrier

PSA:

Polar surface area

ATChI:

Acetythiolcholine iodide

BuChI:

Butyrylcholine iodide

DTNB:

5:5-Dithiobis-2-nitrobenzoic acid

ADME:

Absorption, distribution, metabolism and excretion

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Funding

This work was supported by FRGS, Guru Gobind Singh Indraparatha University, New Delhi, India.

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Authors and Affiliations

  1. University School of Biotechnology, Guru Gobind Singh Indraprastha University, Dwarka, Sector 16C, New Delhi, 110078, India

    Shivani Kumar & Suresh Kumar

  2. University School of Basic and Applied Sciences, Guru Gobind Singh Indraprastha University, Dwarka, Sector 16C, New Delhi, 110078, India

    Yogesh Kumar Tyagi

  3. Department of Biophysics, All India Institute of Medical Sciences, New Delhi, 110029, India

    Manoj Kumar

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  1. Shivani Kumar
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Kumar, S., Tyagi, Y.K., Kumar, M. et al. Synthesis of novel 4-methylthiocoumarin and comparison with conventional coumarin derivative as a multi-target-directed ligand in Alzheimer’s disease. 3 Biotech 10, 509 (2020). https://doi.org/10.1007/s13205-020-02481-1

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