Design, synthesis and docking study of novel coumarin ligands as potential selective acetylcholinesterase inhibitors (original) (raw)
Related papers
Synthesis and evaluation of 4-substituted coumarins as novel acetylcholinesterase inhibitors
European Journal of Medicinal Chemistry, 2013
A series of 4-hydroxycoumarin derivatives were designed and synthesized as new acetylcholinesterase (AChE) inhibitors which could be considered for Alzheimer's disease therapeutics. Among the 19 coumarin-derived compounds tested toward Electrophorus electricus acetylcholinesterase (eelAChE) and horse serum butyrylcholinesterase (eqBChE), N-(1-benzylpiperidin-4-yl)acetamide derivative 4m displayed highest AChE inhibitory activity (IC 50 ¼ 1.2 mM) and good selectivity (37 times). The docking study of the most potent compound 4m, indicated that Phe330 is responsible for ligand recognition and trafficking by forming p-cation interaction with benzylpiperidine moiety. Furthermore, the formation of an additional pep interaction between coumarin moiety and Trp279 of peripheral anionic site could stabilize the ligand in the active site resulting in more potent inhibition of the enzyme.
Bioorganic & Medicinal Chemistry Letters, 2015
New isoconessimine derivatives were synthesized from conessine (1) and evaluated as acetylcholinesterase (AChE) inhibitors. The derivatives were prepared via two reaction steps, N-demethylation and nucleophilic substitution. All of the synthesized derivatives exhibited more potential anti-acetylcholinesterase activities than conessine (1) (IC 50 ＝16 μmol•L-1) and isoconessimine (2) (IC 50 ＞300 μmol•L-1). Compound 7b (3β-[methyl-[2-(4-nitrophenoxy)ethyl]amino]con-5-enine) showed the most potent inhibitory activity with an IC 50 of 110 nmol/L which is close to that of reference compound huperzine A (IC 50 ＝70 nmol/L). The mode of AChE inhibition by 7b was reversible and non-competitive. In addition, molecular modeling was performed to explore the binding mode of inhibitor 7b at the active site of AChE and the results showed that 7b could be docked into the acetylcholinesterase active site and compound 7b had hydrophobic interactions with Trp279 and Leu282.
Indonesian Journal of Chemistry, 2022
Novel benzo[f]coumarin derivatives bearing pyrimidine unit were successfully synthesized. The target is to develop novel acetylcholinesterase inhibitors. The benzo[f]coumarin chalcone 4 was prepared via Claisen-Schmidt condensation between 3-acetyl-5,6-benzocoumarin and 4-hydroxybenzaldehyde in the alkaline medium. Then, the cyclocondensation of chalcone 4 with urea, thiourea, and guanidine HCl in the presence of glacial acetic acid led to the formation of various pyrimidines. Structures of the newly synthesized compounds were characterized by FT-IR, 1 H-NMR, 13 C-NMR spectra, and elemental analysis. The acetylcholinesterase (AChE) inhibitory activity tests were carried out using Ellman's assay and donepezil as a reference drug. The biological activity results revealed that the derivatives 6 and 7 inhibit AChE activity in healthy samples showed that the greater inhibition percentage was found respectively at concentrations of 10-4 and 10-10 M while low inhibition percentage was obtained at 10-12 and 10-4 M. AChE showed inhibition constant Ki in the range of 10-4 −10-12 M in the presence of maximum and minimum inhibitor concentrations, probably due to variant types of inhibition from non and uncompetitive. In addition, molecular modeling simulations of targeted compounds revealed their mechanism of action as potent inhibitors for the AChE enzyme.
Journal of Biomolecular Structure and Dynamics, 2018
The inhibitory efficacy of two substituted coumarin derivatives on the activity of neurodegenerative enzyme acetylcholinesterase (AChE) was assessed in aqueous buffer as well as in the presence of human serum albumin (HSA) and compared against standard cholinergic AD drug, Donepezil (DON). The experimental data revealed the inhibition to be of noncompetitive type with both the systems showing substantial inhibitory activity on AChE. In fact, one of the tested compounds Chromenyl Coumarate (CC) was found to be better inhibitor (IC 50 = 48.49 ± 5.6 nM) than the reference drug DON (IC 50 = 74.13 ± 8.3 nM), unequivocally amplifying its importance. The structure of the compound was found to play a vital role in the inhibitory efficiency, validating previous Structure Activity Relationship (SAR) reviews for coumarin. The mechanism of inhibition remained impervious when the experimental medium was switched from aqueous buffer to HSA, albeit noticeable change in the inhibition potency of the compound 3, 3'-Methylene-bis (4-hydroxy coumarin) (MHC) (38%) and CC (35%). Both the coumarin derivatives were observed to bind to the peripheral anionic site (PAS) of AChE and also found to displace the fluorescence marker thioflavinT (ThT) from AChE binding pocket. All experimental observations were seconded by molecular docking and MD simulation results. The inferences drawn in this study form a foundation for further investigation on these compounds; magnifying the probability of their usage as AD drugs and re-emphasizes the significance of drug delivery media while considering the inhibition potencies of targeted drugs.
International journal of biological macromolecules, 2017
A novel series of acridine-coumarin hybrids was synthesized and biologically evaluated for their potential inhibitory effect on both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The newly synthesized derivatives 9a-d have shown higher activity against human AChE (hAChE) compared with 7-MEOTA as the standard drug. Among them derivative 9b exhibited the most potent acetylcholinesterase inhibitory activity, with an IC50 value of 5.85μM compared with 7-MEOTA (IC50=15μM). Molecular modelling studies were performed to predict the binding modes of compounds 9b, 9c and 9f with hAChE/hBuChE.
Bioorganic & Medicinal Chemistry, 2012
A novel series of coumarin derivatives linked to benzyl pyridinium group were synthesized and biologically evaluated as inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The enzyme inhibitory activity of synthesized compounds was measured using colorimetric Ellman's method. It was revealed that compounds 3e, 3h, 3l, 3r and 3s have shown higher activity compared with donepezil hydrochloride as standard drug. Most of the compounds in these series had nanomolar range IC 50 in which compound 3r (IC 50 = 0.11 nM) was the most active compound against acetylcholinesterase enzyme.
ISRN pharmacology, 2012
Inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is considered a promising strategy for the treatment of Alzheimer's disease (AD). This research project aims to provide a comprehensive knowledge of newly synthesized coumarin analogues with anti-AD potential. In the present work a series of 3-thiadiazolyl- and thioxo-1,2,4-triazolylcoumarins derivatives were designed, synthesized, and tested as potent inhibitors of cholinesterases. These compounds were assayed against AChE from electrophorus electricus and rabbit; and BChE from horse serum and rabbit by Ellman's method using neostigmine methylsulphate and donepezil as reference drugs. Some of the assayed compounds proved to be potent inhibitors of AChE and BChE with K(i) values in the micromolar range. 4b was found to be the most active compound with K(i) value 0.028 ± 0.002 μM and higher selectivity for AChE/BChE. The ability of 4b to interact with AChE was further confirmed through computational st...
Journal of the Brazilian Chemical Society, 2016
Coumarins are a large class of compounds that display a range of interesting biological properties, being considered privileged structures because of the ability of their 2H-chromen-2-one nuclei to bind to multiple pharmacological targets. We hypothesized that the linkage of a second pharmacophore nucleus to the 2H-chromen-2-one core, the 1,2,3-triazole moiety, would entail more selective and pharmacologically active coumarins. Therefore, we describe the synthesis of fourteen 4-methylcoumarins/1,4-substituted 1,2,3-triazole conjugates, which were predicted by in silico methods to inhibit acetylcholinesterase (AChE) and proved to be moderate in vitro inhibitors of this enzyme. Molecular docking simulations suggest that the most active of these compounds has a putative binding mode similar to donepezil, both occupying the peripheral anionic site of AChE, which is associated with the secondary noncholinergic functions of the enzyme. This highlights the potential of this series for further optimization in the search of new coumarins for the treatment of Alzheimer's disease.
Journal of Enzyme Inhibition and Medicinal Chemistry
A series of 3-substituted-7-aminoalcoxy-coumarin was designed and evaluated as cholinesterase inhibitors and antioxidants. All compounds were effective in inhibiting AChE with potencies in the nanomolar range. The 3-(4-(dimethylamino)phenyl)-7-aminoethoxy-coumarin (6a) was considered a hit, showing good AChE inhibition potency (IC 50 ¼ 20 nM) and selectivity (IC 50 BuChE/AChE ¼ 354), quite similar to the reference drug donepezil (IC 50 ¼ 6 nM; IC 50 BuChE/AChE ¼ 365), also presenting antioxidant properties, low citotoxicity and good-predicted ADMET properties. The mode of action (mixed-type) and SAR analysis for this series of compounds were described by means of kinetic and molecular modeling evaluations.
ChemMedChem, 2017
Acetylcholinesterase (AChE) inhibitors still comprise the majority of the marketed drugs for Alzheimer's disease (AD). The structural arrangement of the enzyme, which features a narrow gorge that separates the catalytic and peripheral anionic subsites (CAS and PAS, respectively), inspired the development of bivalent ligands that are able to bind and block the catalytic activity of the CAS as well as the role of the PAS in beta amyloid (Aβ) fibrillogenesis. With the aim of discovering novel AChE dual binders with improved drug-likeness, homo- and heterodimers containing 2H-chromen-2-one building blocks were developed. By exploring diverse linkages of neutral and protonatable amino moieties through aliphatic spacers of different length, a nanomolar bivalent AChE inhibitor was identified (3-[2-({4-[(dimethylamino)methyl]-2-oxo-2H-chromen-7-yl}oxy)ethoxy]-6,7-dimethoxy-2H-chromen-2-one (6 d), IC50 =59 nm) from originally weakly active fragments. To assess the potential against AD, t...