Multi-target potential of newly designed tacrine-derived cholinesterase inhibitors: Synthesis, computational and pharmacological study
2024
Authors:
Jevtić, Ivana I.Suručić, Relja V.
Tovilović-Kovačević, Gordana
Zogović, Nevena
Kostić-Rajačić, Slađana V.
Andrić, Deana
Penjišević, Jelena Z.
Document Type:
Article (Accepted Version)
,
© 2024 by Elsevier
Metadata
Show full item recordAbstract:
Simple and scalable synthetic approach was used for the preparation of thirteen novel tacrine derivatives consisting of tacrine and N-aryl-piperidine-4-carboxamide moiety connected by a five-methylene group linker. An anti-Alzheimer disease (AD) potential of newly designed tacrine derivatives was evaluated against two important AD targets, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). In vitro pharmacological evaluation showed strong ChE inhibitory activity of all compounds, with IC50 values ranging from 117.5 to 455 nM for AChE and 34 to 324 nM for BuChE. As a representative of the series with the best cytotoxicity / ChE inhibitory activity ratio, expressed as the selectivity index (SI), 2-chlorobenzoyl derivative demonstrated mixed-type inhibition on AChE and BuChE, suggesting binding to both CAS and PAS of the enzymes. It also exhibited antioxidant capacity and neuroprotective potential against amyloid-β (Aβ) toxicity in the culture of neuron-like cells. In-depth computational analysis corroborated well with in vitro ChE inhibition, illuminating that all compounds exhibit significant potential in targeting both enzymes. Molecular dynamics (MD) simulations revealed that 2-chlorobenzoyl derivative, created complexes with AChE and BuChE that demonstrated sufficient stability throughout the observed MD simulation. Computationally predicted ADME properties indicated that these compounds should have good blood–brain barrier (BBB) permeability, an important factor for CNS-targeting drugs. Overall, all tested compounds showed promising pharmacological behavior, highlighting the multi-target potential of 2- chlorobenzoyl derivative which should be further investigated as a new lead in the drug development process.
Note:
This is the accepted manuscript version of the following article: Jevtić II, Suručić RV, Tovilović-Kovačević G, Zogović N, Kostić-Rajačić SV, Andrić DB, Penjišević JZ. Multi-target potential of newly designed tacrine-derived cholinesterase inhibitors: Synthesis, computational and pharmacological study. Bioorg Med Chem. 2024;101:117649. http://dx.doi.org/10.1016/j.bmc.2024.117649
Keywords:
Alzheimer’s disease; Tacrine; Piperidine-4-carboxamide; Cholinesterase; Cytotoxicity; Neuroprotection; Molecular docking; Molecular dynamics; ADMESource:
Bioorganic & Medicinal Chemistry, 2024, 101, 117649-Funding / projects:
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200026 (University of Belgrade, Institute of Chemistry, Technology and Metallurgy - IChTM) (RS-MESTD-inst-2020-200026)
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200168 (University of Belgrade, Faculty of Chemistry) (RS-MESTD-inst-2020-200168)
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200007 (University of Belgrade, Institute for Biological Research 'Siniša Stanković') (RS-MESTD-inst-2020-200007)
Related info:
DOI: 10.1016/j.bmc.2024.117649
ISSN: 0968-0896
PubMed: 38401458
Scopus: 2-s2.0-85185942192
URI
https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4662547http://radar.ibiss.bg.ac.rs/handle/123456789/6648