New insights into butyrylcholinesterase: Pharmaceutical applications, selective inhibitors and multitarget-directed ligands

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 275, P. 116569 - 116569

Published: June 5, 2024

Language: Английский

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Analysis of skeletal diversity of multi-target directed ligands (MTDLs) targeting Alzheimer’s disease

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 286, P. 117277 - 117277

Published: Jan. 18, 2025

Language: Английский

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Discovery and In Vivo Proof of Concept of a Highly Potent Dual Inhibitor of Soluble Epoxide Hydrolase and Acetylcholinesterase for the Treatment of Alzheimer’s Disease

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(6), P. 4909 - 4925

Published: March 10, 2022

With innumerable clinical failures of target-specific drug candidates for multifactorial diseases, such as Alzheimer's disease (AD), which remains inefficiently treated, the advent multitarget discovery has brought a new breath hope. Here, we disclose class 6-chlorotacrine (huprine)-TPPU hybrids dual inhibitors enzymes soluble epoxide hydrolase (sEH) and acetylcholinesterase (AChE), profile to provide cumulative effects against neuroinflammation memory impairment. Computational studies confirmed gorge-wide occupancy both enzymes, from main site secondary site, including so far non-described AChE cryptic pocket. The lead compound displayed in vitro nanomolar potencies, adequate brain permeability, aqueous solubility, human microsomal stability, lack neurotoxicity, it rescued memory, synaptic plasticity, an AD mouse model, after low dose chronic oral administration.

Language: Английский

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Synthesis of novel benzothiazole derivatives and investigation of their enzyme inhibitory effects against Alzheimer's disease

RSC Advances, Journal Year: 2022, Volume and Issue: 12(36), P. 23626 - 23636

Published: Jan. 1, 2022

The use of dual acetylcholinesterase (AChE)-monoamine oxidase B (MAO-B) inhibitors is a new approach in the treatment Alzheimer disease (AD). In this work, 14 benzothiazoles (4a-4n) were designed and synthesized. biological activity studies, AChE, butyrylcholinesterase (BChE), MAO-A MAO-B inhibitory potentials all compounds evaluated using

Language: Английский

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Morphing cholinesterase inhibitor amiridine into multipotent drugs for the treatment of Alzheimer's disease

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 173, P. 116399 - 116399

Published: March 15, 2024

The search for novel drugs to address the medical needs of Alzheimer's disease (AD) is an ongoing process relying on discovery disease-modifying agents. Given complexity disease, such aim can be pursued by developing so-called multi-target directed ligands (MTDLs) that will impact pathophysiology more comprehensively. Herewith, we contemplated therapeutic efficacy amiridine drug acting as a cholinesterase inhibitor converting it into class MTDLs. Applying linking approach, have paired core building block with memantine/adamantylamine, trolox, and substituted benzothiazole moieties generate MTDLs endowed additional properties like N-methyl-d-aspartate (NMDA) receptor affinity, antioxidant capacity, anti-amyloid properties, respectively. top-ranked amiridine-based compound 5d was also inspected in silico reveal butyrylcholinesterase binding differences its close structural analogue 5b. Our study provides insight broadening their target-engaged profile from inhibitors towards potential implications AD therapy.

Language: Английский

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Design, synthesis and molecular docking and ADME studies of novel hydrazone derivatives for AChE inhibitory, BBB permeability and antioxidant effects

Journal of Biomolecular Structure and Dynamics, Journal Year: 2022, Volume and Issue: 41(18), P. 9022 - 9038

Published: Nov. 3, 2022

Alzheimer's disease (AD) is a progressive and fatal neurodegenerative that characterized by memory cognitive impairments predominantly affects the elderly most common cause of dementia. As known, AChE enzyme consists two parts. In this work, 10 new hydrazones (3a-3j) were designed synthesized. Naphthalene, indole, benzofuran benzothiophene rings used to interact with PAS region. 4-fluorophenyl 4-fluorobenzyl structures preferred for interaction CAS biological activity studies, BChE inhibitory potentials all compounds evaluated using in vitro Ellman method. The evaluation showed 3i 3j displayed significant against AChE. IC50 values 0.034 0.027 µM AChE, respectively. reference drug donepezil (IC50 = 0.021 µM) also inhibition addition, antioxidant activities evaluated. Derivatives 3j, which emerged active from both subjected PAMPA tests determine BBB permeability. Further docking simulation revealed these (3i, donepezil) interacted site similar manner donepezil. A few parameters derived MD trajectories computed validated protein-ligand complex's stability under dynamic conditions.Communicated Ramaswamy H. Sarma.

Language: Английский

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RETRACTED: Hesperidin methylchalcone (HMC) hinders amyloid-β induced Alzheimer's disease by attenuating cholinesterase activity, macromolecular damages, oxidative stress and apoptosis via regulating NF-κB and Nrf2/HO-1 pathways

International Journal of Biological Macromolecules, Journal Year: 2023, Volume and Issue: 233, P. 123169 - 123169

Published: Jan. 6, 2023

Language: Английский

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Potential of Tryptamine Derivatives as Multi-Target Directed Ligands for Alzheimer’s Disease: AChE, MAO-B, and COX-2 as Molecular Targets

Molecules, Journal Year: 2024, Volume and Issue: 29(2), P. 490 - 490

Published: Jan. 19, 2024

Extensive research has been dedicated to develop compounds that can target multiple aspects of Alzheimer's disease (AD) treatment due a growing understanding AD's complex multifaceted nature and various interconnected pathological pathways. In the present study, series biological assays were performed evaluate potential tryptamine analogues synthesized earlier in our lab as multi-target-directed ligands (MTDLs) for AD. To assess inhibitory effects compounds, vitro employed. Three

Language: Английский

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Effects of Linkers and Substitutions on Multitarget Directed Ligands for Alzheimer’s Diseases: Emerging Paradigms and Strategies

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(11), P. 6085 - 6085

Published: May 29, 2022

Alzheimer's disease (AD) is multifactorial, progressive and the most predominant cause of cognitive impairment dementia worldwide. The current "one-drug, one-target" approach provides only symptomatic relief to condition but unable cure completely. conventional single-target therapeutic might not always induce desired effect due multifactorial nature AD. Hence, multitarget strategies have been proposed simultaneously knock out multiple targets involved in development Herein, we provide an overview various strategies, followed by multitarget-directed ligand (MTDL) development, rationale designs efficient examples. Furthermore, effects linkers substitutional functional groups on MTDLs against AD their modes action are also discussed.

Language: Английский

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Bis-Amiridines as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: N-Functionalization Determines the Multitarget Anti-Alzheimer’s Activity Profile

Molecules, Journal Year: 2022, Volume and Issue: 27(3), P. 1060 - 1060

Published: Feb. 4, 2022

Using two ways of functionalizing amiridine-acylation with chloroacetic acid chloride and reaction thiophosgene-we have synthesized new homobivalent bis-amiridines joined by different spacers-bis-N-acyl-alkylene (3) bis-N-thiourea-alkylene (5) -as potential multifunctional agents for the treatment Alzheimer's disease (AD). All compounds exhibited high inhibitory activity against acetylcholinesterase (AChE) butyrylcholinesterase (BChE) selectivity BChE. These displayed negligible carboxylesterase inhibition, suggesting a probable lack untoward drug-drug interactions arising from hydrolytic biotransformation. Compounds 3 bis-N-acyl-alkylene spacers were more potent inhibitors both cholinesterases compared to 5 parent amiridine. The lead 3a-c an IC50(AChE) = 2.9-1.4 µM, IC50(BChE) 0.13-0.067 14-18% propidium displacement at 20 μM. Kinetic studies 3a 5d indicated mixed-type reversible inhibition. Molecular docking revealed favorable poses in catalytic peripheral AChE sites. Propidium site hybrids suggests their hinder AChE-assisted Aβ42 aggregation. Conjugates had no effect on self-aggregation, whereas 5c-e (m 4, 5, 6) showed mild (13-17%) greatest difference between conjugates was antioxidant activity. Bis-amiridines N-acylalkylene nearly inactive ABTS FRAP tests, thiourea demonstrated activity, especially test (TEAC 1.2-2.1), agreement significantly lower HOMO-LUMO gap values. Calculated ADMET parameters all predicted blood-brain barrier permeability intestinal absorption, as well low propensity cardiac toxicity. Thus, it possible obtain amiridine derivatives whose potencies BChE equaled or exceeded that compound, Overall, based expanded balanced pharmacological profiles, appear promising future optimization development multitarget anti-AD agents.

Language: Английский

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