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Amiridine-piperazine hybrids as cholinesterase inhibitors and potential multitarget agents for Alzheimer’s disease treatment.
Abstract: We synthesized eleven new amiridine-piperazine hybrids 5a-j and 7 as potential multifunctional agents for Alzheimer's disease (AD) treatment by reacting N-chloroacetylamiridine with piperazines. The compounds displayed mixed-type reversible inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Conjugates were moderate inhibitors of equine and human BChE with negligible fluctuation in anti-BChE activity, whereas anti-AChE activity was substantially dependent on N4-substitution of the piperazine ring. Compounds with para-substituted aromatic moieties (5g, 5h, and bis-amiridine 7) had the highest anti-AChE activity in the low micromolar range. Top-ranked compound 5h, N-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-9-yl)-2-[4-(4-nitro-phenyl)-piperazin-1-yl]-acetamide, had an IC for AChE = 1.83 ± 0.03 μM (K = 1.50 ± 0.12 and αK = 2.58 ± 0.23 μM). The conjugates possessed low activity against carboxylesterase, indicating a likely absence of unwanted drug-drug interactions in clinical use. In agreement with analysis of inhibition kinetics and molecular modeling studies, the lead compounds were found to bind effectively to the peripheral anionic site of AChE and displace propidium, indicating their potential to block AChE-induced β-amyloid aggregation. Similar propidium displacement activity was first shown for amiridine. Two compounds, 5c (R = cyclohexyl) and 5e (R = 2-MeO-Ph), exhibited appreciable antioxidant capability with Trolox equivalent antioxidant capacity values of 0.47 ± 0.03 and 0.39 ± 0.02, respectively. Molecular docking and molecular dynamics simulations provided insights into the structure-activity relationships for AChE and BChE inhibition, including the observation that inhibitory potencies and computed pK values of hybrids were generally lower than those of the parent molecules. Predicted ADMET and physicochemical properties of conjugates indicated good CNS bioavailability and safety parameters comparable to those of amiridine and therefore acceptable for potential lead compounds at the early stages of anti-AD drug development.
Copyright © 2021 Elsevier Inc. All rights reserved.
Publication Date: 2021-05-21 PubMed ID: 34029971DOI: 10.1016/j.bioorg.2021.104974Google Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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This research article focused on the synthesis of new compounds, amiridine-piperazine hybrids, and their potential as inhibitors of enzymes associated with Alzheimer’s disease. It was found that these compounds show promising activity against key enzymes and have antioxidant capabilities, making them potential candidates for developing treatment drugs for Alzheimer’s disease.
Synthesis of Amiridine-Piperazine Hybrids
- The team synthesized eleven new amiridine-piperazine hybrids as potential treatment agents for Alzheimer’s disease by reacting N-chloroacetylamiridine with piperazines.
Inhibition of Cholinesterase Enzymes
- The new compounds displayed mixed-type reversible inhibition of two important enzymes: acetylcholinesterase (AChE) and butyrylcholinesterase (BChE).
- Anti-BChE activity didn’t show significant fluctuation, while anti-AChE activity largely depended on the N4-substitution of the piperazine ring.
- Among these, compounds with para-substituted aromatic moieties showed the highest anti-AChE activity.
Analysis of Other Activities
- The hybrids showed low activity against carboxylesterase, thereby indicating a likely absence of unwanted drug-drug interactions in clinical use.
- The lead compounds were found to bind effectively with the peripheral anionic site of AChE and displace propidium — first shown for amiridine, this indicates their potential to block AChE-induced β-amyloid aggregation, a key characteristic in Alzheimer’s disease pathogenesis.
- Two compounds exhibited significant antioxidant capability, a beneficial attribute in countering oxidative stress associated with neurodegenerative diseases.
Molecular Docking and Dynamics Simulations
- Molecular docking and dynamics simulations gave insights into the relationships between the structure of the synthesized compounds and their enzyme inhibition activity.
- The inhibitory potencies and computed pK values of hybrids were generally lower than those of the parent molecules.
Predicted ADMET and Physicochemical Properties
- After studying the pharmacokinetics and toxicity, the researchers found that the new compounds have good bioavailability in the central nervous system (CNS) and safety parameters comparable to amiridine, making them suitable candidates for early stage anti-Alzheimer’s drug development.
Cite This Article
APA
Makhaeva GF, Lushchekina SV, Kovaleva NV, Yu Astakhova T, Boltneva NP, Rudakova EV, Serebryakova OG, Proshin AN, Serkov IV, Trofimova TP, Tafeenko VA, Radchenko EV, Palyulin VA, Fisenko VP, Korábečný J, Soukup O, Richardson RJ.
(2021).
Amiridine-piperazine hybrids as cholinesterase inhibitors and potential multitarget agents for Alzheimer’s disease treatment.
Bioorg Chem, 112, 104974.
https://doi.org/10.1016/j.bioorg.2021.104974 Publication
Researcher Affiliations
- Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka 142432, Russia.
- Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka 142432, Russia; Emanuel Institute of Biochemical Physics Russian Academy of Sciences, Moscow 119334, Russia.
- Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka 142432, Russia.
- Emanuel Institute of Biochemical Physics Russian Academy of Sciences, Moscow 119334, Russia.
- Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka 142432, Russia.
- Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka 142432, Russia.
- Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka 142432, Russia.
- Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka 142432, Russia.
- Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka 142432, Russia.
- Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka 142432, Russia; Department of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russia.
- Department of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russia.
- Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka 142432, Russia; Department of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russia.
- Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka 142432, Russia; Department of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russia.
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow 119881, Russia.
- Biomedical Research Centre, University Hospital Hradec Kralove, 500 05 Hradec Kralove, Czech Republic.
- Biomedical Research Centre, University Hospital Hradec Kralove, 500 05 Hradec Kralove, Czech Republic.
- Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI 48109 USA; Department of Neurology, University of Michigan, Ann Arbor, MI 48109 USA; Center of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109 USA. Electronic address: rjrich@umich.edu.
MeSH Terms
- Acetylcholinesterase / metabolism
- Alzheimer Disease / drug therapy
- Alzheimer Disease / metabolism
- Aminoquinolines / chemistry
- Aminoquinolines / pharmacology
- Animals
- Antioxidants / chemical synthesis
- Antioxidants / chemistry
- Antioxidants / pharmacology
- Benzothiazoles / antagonists & inhibitors
- Butyrylcholinesterase / metabolism
- Cholinesterase Inhibitors / chemical synthesis
- Cholinesterase Inhibitors / chemistry
- Cholinesterase Inhibitors / pharmacology
- Dose-Response Relationship, Drug
- Horses
- Humans
- Models, Molecular
- Molecular Structure
- Neuroprotective Agents / chemical synthesis
- Neuroprotective Agents / chemistry
- Neuroprotective Agents / pharmacology
- Oxidative Stress / drug effects
- Piperazine / chemistry
- Piperazine / pharmacology
- Structure-Activity Relationship
- Sulfonic Acids / antagonists & inhibitors
Citations
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