Multi-target potential of newly designed tacrine-derived cholinesterase inhibitors: Synthesis, computational and pharmacological study
2024
Autori:
Jevtić, Ivana I.Suručić, Relja V.
Tovilović-Kovačević, Gordana
Zogović, Nevena
Kostić-Rajačić, Slađana V.
Andrić, Deana
Penjišević, Jelena Z.
Tip dokumenta:
Članak u časopisu (Recenzirana verzija)
,
© 2024 by Elsevier
Metapodaci
Prikaz svih podataka o dokumentuApstrakt:
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.
Napomena:
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
Ključne reči:
Alzheimer’s disease; Tacrine; Piperidine-4-carboxamide; Cholinesterase; Cytotoxicity; Neuroprotection; Molecular docking; Molecular dynamics; ADMEIzvor:
Bioorganic & Medicinal Chemistry, 2024, 101, 117649-Finansiranje / projekti:
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200026 (Univerzitet u Beogradu, Institut za hemiju, tehnologiju i metalurgiju - IHTM) (RS-MESTD-inst-2020-200026)
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200168 (Univerzitet u Beogradu, Hemijski fakultet) (RS-MESTD-inst-2020-200168)
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200007 (Univerzitet u Beogradu, Institut za biološka istraživanja 'Siniša Stanković') (RS-MESTD-inst-2020-200007)
Povezane informacije:
- Druga verzija
https://radar.ibiss.bg.ac.rs/handle/123456789/6629
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