Discovery of new, highly potent and selective inhibitors of BuChE - design, synthesis, in vitro and in vivo evaluation and crystallography studies

Panek, Dawid; Pasieka, Anna; Latacz, Gniewomir; Zaręba, Paula; Szczęch, Michał; Godyń, Justyna; Chantegreil, Fabien; Nachon, Florian; Brazzolotto, Xavier; Skrzypczak-Wiercioch, Anna; Walczak, Maria; Smolik, Magdalena; Sałat, Kinga; Höfner, Georg; Wanner, Klaus T.; Więckowska, Anna; Malawska, Barbara

doi:10.1016/j.ejmech.2023.115135

Cited by 9 publications

(4 citation statements)

References 47 publications

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“…The direct connection between the etiopathogenesis of the disease and the procognitive effects of selective BChE inhibitors has been substantiated by their application in animal models. 48 Additionally, BChE expression aligns with Aβ aggregation, in parallel with senile plaque formation and maturation. 49,50 Studies in BChE knockout mice have shown reduced Aβ plaque deposition.…”

Section: Introductionmentioning

confidence: 98%

Carltonine-derived compounds for targeted butyrylcholinesterase inhibition

Pidany,

Kroustkova,

Jenco

et al. 2024

RSC Med. Chem.

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Section: Introductionmentioning

confidence: 98%

Carltonine-derived compounds for targeted butyrylcholinesterase inhibition

Pidany,

Kroustkova,

Jenco

et al. 2024

RSC Med. Chem.

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“…BChE produced by reactive astrocytes can worsen cognitive function by accelerating the degradation of acetylcholine in the aging brain . Therefore, developing selective BChE inhibitors is an essential strategy for treating AD, and the main side effects of AChE inhibitors would not be reproduced. − …”

Section: Introductionmentioning

confidence: 99%

Discovery, Structure-Based Modification, In Vitro, In Vivo, and In Silico Exploration of m-Sulfamoyl Benzoamide Derivatives as Selective Butyrylcholinesterase Inhibitors for Treating Alzheimer’s Disease

Lu,

Li,

Guan

et al. 2024

ACS Chem. Neurosci.

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For the potential therapy of Alzheimer's disease (AD), butyrylcholinesterase (BChE) has gradually gained worldwide interest in the progression of AD. This study used a pharmacophore-based virtual screening (VS) approach to identify Z32439948 as a new BChE inhibitor. Aiding by molecular docking and molecular dynamics, essential binding information was disclosed. Specifically, a subpocket was found and structure-guided design of a series of novel compounds was conducted. Derivatives were evaluated in vitro for cholinesterase inhibition and physicochemical properties (BBB, log P, and solubility). The investigation involved docking, molecular dynamics, enzyme kinetics, and surface plasmon resonance as well. The study highlighted compounds 27a (hBChE IC 50 = 0.078 ± 0.03 μM) and (R)-37a (hBChE IC 50 = 0.005 ± 0.001 μM) as the top-ranked BChE inhibitors. These compounds showed anti-inflammatory activity and no apparent cytotoxicity against the human neuroblastoma (SH-SY5Y) and mouse microglia (BV2) cell lines. The most active compounds exhibited the ability to improve cognition in both scopolamine-and Aβ 1−42 peptide-induced cognitive deficit models. They can be promising lead compounds with potential implications for treating the late stage of AD.

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“…As the disease progresses in the AD brain, BChE activity increases and eventually replaces AChE (Chen et al, 2017; Li et al, 2020). As a result, BChE inhibition has received increased attention in recent AD drug development studies (Jing et al, 2019; Panek et al, 2023). Therefore, ChE continues to be the principal biological target for the development of MTDLs, typically combining ChE inhibitory activity with activity against disease‐modifying or neuroprotective targets (Wichur et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and investigation of the cholinesterase inhibitory and antioxidant capacities of some novel N'‐(quinolin‐4‐ylmethylene)propanehydrazides against Alzheimer's disease

Kilic,

Dogruer

2024

Drug Development Research

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One of the worst long‐term health issues of the past few decades is Alzheimer's disease (AD). Unfortunately, there are currently insufficient choices for treating and caring for AD, which makes it a popular subject for drug development research. Studies on the development of drugs for AD have primarily concentrated on the use of multitarget directed ligands. Following this strategy, we designed new ChE inhibitors with additional antioxidant and metal chelator effects. In this research, eight novel N’‐(quinolin‐4‐ylmethylene)propanehydrazide derivatives were synthesized and characterized. We then evaluated the inhibition potency of all the final compounds for cholinesterase enzymes. Among them, 4e (IC50 acetylcholinesterase [AChE] = 0.69 µM and butyrylcholinesterase [BChE]= 26.00 µM) and 4h (IC50's AChE= 7.04 µM and BChE= 16.06 µM) were found to be the most potent AChE and BChE inhibitors, respectively.

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Discovery of new, highly potent and selective inhibitors of BuChE - design, synthesis, in vitro and in vivo evaluation and crystallography studies

Cited by 9 publications

References 47 publications

Carltonine-derived compounds for targeted butyrylcholinesterase inhibition

Carltonine-derived compounds for targeted butyrylcholinesterase inhibition

Discovery, Structure-Based Modification, In Vitro, In Vivo, and In Silico Exploration of m-Sulfamoyl Benzoamide Derivatives as Selective Butyrylcholinesterase Inhibitors for Treating Alzheimer’s Disease

Synthesis and investigation of the cholinesterase inhibitory and antioxidant capacities of some novel N'‐(quinolin‐4‐ylmethylene)propanehydrazides against Alzheimer's disease

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