Discovery of multifunctional anti-Alzheimer’s agents with a unique mechanism of action including inhibition of the enzyme butyrylcholinesterase and γ-aminobutyric acid transporters

Pasieka, Anna; Panek, Dawid; Jończyk, Jakub; Godyń, Justyna; Szałaj, Natalia; Latacz, Gniewomir; Tabor, Julia; Mezeiová, Eva; Chantegreil, Fabien; Dias, José; Knez, Damijan; Lu, Junfeng; Korábečný, Jan; Brazzolotto, Xavier; Gobec, Stanislav; Höfner, Georg; Wanner, Klaus T.; Więckowska, Anna; Malawska, Barbara

doi:10.1016/j.ejmech.2021.113397

Cited by 18 publications

(4 citation statements)

References 105 publications

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“…Structural information is available for the binding of many reversible ligands to hAChE (huprine W, PDB id: 21 ), Tc AChE (huprine X, ; 24 a tacrine derivative, 22 ), and to hBuChE (tacrine, ; 21 huprine 19, ; thioflavin T, ; decamethonium, ; ethopropazine, ; propidium, ; 23 a hydroxyethylamine derivative, ; 18 a tacrine-methyl anacardate hybrid, ; 25 or compounds 6QS and 3F9 designed by virtual screening, 20 and 26 ). A crystal structure of a fully glycosylated hBuChE without a ligand has also been obtained ().…”

Section: Resultsmentioning

confidence: 99%

“…Molecular docking is a well-established tool for interpreting experimentally determined inhibitory abilities of newly synthesised ligands, [17][18][19] or even for virtual screening campaigns leading to suggestions for synthesis. 20 Herein, we used this tool to compare docked poses and binding free energies of our molecules with those of known reference ligands in crystal structures of human acetyl-and butyrylcholinesterase.…”

Section: Molecular Docking Studiesmentioning

confidence: 99%

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Synthesis and cholinesterase inhibitory activity study of Amaryllidaceae alkaloid analogues with N-methyl substitution

et al. 2022

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Section: Resultsmentioning

confidence: 99%

Section: Molecular Docking Studiesmentioning

confidence: 99%

Synthesis and cholinesterase inhibitory activity study of Amaryllidaceae alkaloid analogues with N-methyl substitution

et al. 2022

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“…The complexes of AChE (chain A; PDB code 6O4W) [ 35 ], BChE (PDB code 7BGC) [ 36 ], and FAAH (PDB code 4DO3) with the proper inhibitor were selected as targets for docking [ 37 ]. The X-ray structures were prepared for dockings with the Protein Preparation Wizard interface of Maestro: the ligand and water molecules were removed, while hydrogen atoms were added and their positions were optimized [ 38 , 39 , 40 , 41 ].…”

Section: Methodsmentioning

confidence: 99%

Novel Phenothiazine/Donepezil-like Hybrids Endowed with Antioxidant Activity for a Multi-Target Approach to the Therapy of Alzheimer’s Disease

et al. 2022

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Alzheimer’s disease (AD) is a complex multi-factorial neurodegenerative disorder for which only few drugs (including donepezil, DPZ) are available as symptomatic treatments; thus, researchers are focusing on the development of innovative multi-target directed ligands (MTDLs), which could also alter the course of the disease. Among other pathological factors, oxidative stress has emerged as an important factor in AD that could affect several pathways involved in the onset and progression of the pathology. Herein, we propose a new series of hybrid molecules obtained by linking a phenothiazine moiety, known for its antioxidant properties, with N-benzylpiperidine or N-benzylpiperazine fragments, mimicking the core substructure of DPZ. The investigation of the resulting hybrids showed, in addition to their antioxidant properties, their activity against some AD-related targets, such as the inhibition of cholinesterases (both AChE and BChE) and in vitro Aβ1-40 aggregation, as well as the inhibition of the innovative target fatty acid amide hydrolase (FAAH). Furthermore, the drug-likeness properties of these compounds were assessed using cheminformatic tools. Compounds 11d and 12d showed the most interesting multi-target profiles, with all the assayed activities in the low micromolar range. In silico docking calculations supported the obtained results. Compound 13, on the other hand, while inactive in the DPPH assay, showed the best results in the in vitro antioxidant cell assays conducted on both HepG2 and SHSY-5Y cell lines. These results, paired with the low or absent cytotoxicity of these compounds at tested concentrations, allow us to aim our future research at the study of novel and effective drugs and pro-drugs with similar structural characteristics.

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“…In this follow-up study, the focus was on the development of simple and reliable models, using simple molecular descriptors linked to the molecular key features of BChE inhibitors to estimate their inhibition potency toward BChE. For this purpose, we used a negative logarithm of experimentally determined inhibition potency values p K i or pIC 50 , which for simplicity we denoted by pIn, for 297 structurally different compounds from the literature, including 4-aminoquinolines, coumarins, flavonoids, N-hydroxyiminoacetamides, huprine derivates, oximes, quinuclidines, tacrine derivates and others [ 3 , 8 , 9 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. The range of pIn values for BChE inhibition was 8.6 (2.4–11).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Key Structural Features of Various Butyrylcholinesterase Inhibitors Using Simple Molecular Descriptors

Miličević

Šinko

2022

Molecules

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In this study, we developed several QSAR models based on simple descriptors (such as topological and constitutional) to estimate butyrylcholinesterase (BChE) inhibition potency, pKi (or pIC50), of a set of 297 (289 after exclusion of outliers) structurally different compounds. The models were similar to the best model that we obtained previously for acetylcholinesterase AChE and were based on the valence molecular connectivity indices of second and third order (2χv and 3χv), the number of aliphatic hydroxyl groups (nOH), AlogP Ghose–Crippen octanol–water partition coeff. (logP), and O-060–atom-centred fragments (Al-O-Ar, Ar-O-Ar, R..O..R and R-O-C=X). The best models with two and three descriptors yielded r = 0.787 and S.E. = 0.89, and r = 0.827 and S.E. = 0.81, respectively. We also correlated nine scoring functions, calculated for 20 ligands whose complexes with BChE we found in the Protein Data Bank as crystal structures to pKi (or pIC50). The best correlations yielded PLP1 and PLP2 (Piecewise Linear Pairwise potential functions) with r = 0.619 and 0.689, respectively. Correlation with certain simple topological and constitutional descriptors yielded better results, e.g., 3χv (r = 0.730), on the same set of compounds (N = 20).

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Discovery of multifunctional anti-Alzheimer’s agents with a unique mechanism of action including inhibition of the enzyme butyrylcholinesterase and γ-aminobutyric acid transporters

Cited by 18 publications

References 105 publications

Synthesis and cholinesterase inhibitory activity study of Amaryllidaceae alkaloid analogues with N-methyl substitution

Synthesis and cholinesterase inhibitory activity study of Amaryllidaceae alkaloid analogues with N-methyl substitution

Novel Phenothiazine/Donepezil-like Hybrids Endowed with Antioxidant Activity for a Multi-Target Approach to the Therapy of Alzheimer’s Disease

Evaluation of the Key Structural Features of Various Butyrylcholinesterase Inhibitors Using Simple Molecular Descriptors

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