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

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 (IC 50 -5.63 µM) and butyrylcholinesterase (IC 50 -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. Keywords 4-Methylthiocoumarin derivative • Alzheimer's disease • BACE1 inhibitor • Cholinesterase inhibitor • In silico studies * Suresh Kumar

Thiocoumarins: From the Synthesis to the Biological Applications

“…As several other coumarin derivatives, 4-methylthiocoumarins have been described as a multitarget-directed ligand for the treatment of Alzheimer’s disease [ 49 ]. A novel 4-methylthiocoumarin derivative has been studied against acetylcholinesterase, butyrylcholinesterase, BACE1, β-amyloid aggregation, and oxidative stress involved in the pathogenesis of this neurodegenerative disease.…”

Neuroprotective and Mental Health Benefits of Salt-Tolerant Plants: A Comprehensive Review of Traditional Uses and Biological Properties

“…In AD, both AChE and BuChE are associated with disease pathology, indicating their potential as targets for diagnostic and therapeutic interventions [6]. The development of multi-target-directed ligands, such as 4methylthiocoumarin derivatives, highlights the advancement in AD treatment by inhibiting these enzymes alongside β-amyloid aggregation and oxidative stress [7]. The exploration of novel cholinesterase inhibitors with multi-faceted therapeutic approaches, as reviewed by Saxena [8], emphasizes the need for a comprehensive strategy to address the multifactorial nature of AD [8].…”

An overview of structure-based activity outcomes of pyran derivatives against Alzheimer’s disease

“…Compound (8) was also capable of inhibiting MAO B enzymes to a marginal degree, as well as BACE1 to a moderate degree.The action of the compounds against cholinesterase enzyme, BACE1, A, and oxidative stress appears promising. The IC 50 (µM) at 80 µM concentration for (8) against AChE is 5.63 ± 1.68 and for (9) against BuChE is 3.40 ± 0.20 respectively ( Kumar et al, 2020 ).…”

“… ( Mzezewa et al, 2021 ) 4 0.101 µM (Ellman assay) Potential activity observed due to the inclusion of the propargylamine functional group ( Mzezewa et al, 2021 ) 5 human MAO-B IC 50 = 3.9 nM human MAO-B IC 50 = 4.4 nM (acetylcholine esterase inhibition assay) Substitution of pyrazole on coumarins may show an increase in anti- Alzheimer’s activity ( Narayanan et al, 2021 ) 6 SH-SY5Y cell model The ethoxycarbonyl group increases activity ( Huang et al, 2021 ) 7 Phenyl separated from coumarin by ethylcarbonyl group imparts increased activity ( Huang et al, 2021 ) 8 Ellman assay, FRET assay) The thioxo group and ether linkage increase activity. ( Kumar et al, 2020 ) 9 Ellman assay, FRET assay ( Kumar et al, 2020 ) 10 21.71 μM (Ellman assay) Difluorobenzyl and triazole dimethylamino groups increased activity ( Karimi Askarani et al, 2020 ) 11 2.0 nM (Ellman assay) The choline-binding site was comprised of the phenyl ring, which was coupled to the piperazine ring. ( Abu-Aisheh et al, 2019 ) 12 0.091 ± 0.011 mM (Ellman assay) Benzoylamino-phenyl group results in increased activity ( Hu et al, 2019 ) 13 0.559 ± 0.017 mM (Ellman assay) 14 …”