Multi-target potential of newly designed tacrine-derived cholinesterase inhibitors: Synthesis, computational and pharmacological study
2024
Аутори:
Jevtić, Ivana I.Suručić, Relja V.
Tovilović-Kovačević, Gordana
Zogović, Nevena
Kostić-Rajačić, Slađana V.
Andrić, Deana
Penjišević, Jelena Z.
Тип документа:
Чланак у часопису (Рецензирана верзија)
,
© 2024 by Elsevier
Метаподаци
Приказ свих података о документуАпстракт:
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.
Напомена:
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
Кључне речи:
Alzheimer’s disease; Tacrine; Piperidine-4-carboxamide; Cholinesterase; Cytotoxicity; Neuroprotection; Molecular docking; Molecular dynamics; ADMEИзвор:
Bioorganic & Medicinal Chemistry, 2024, 101, 117649-Финансирање / пројекти:
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200026 (Универзитет у Београду, Институт за хемију, технологију и металургију - ИХТМ) (RS-MESTD-inst-2020-200026)
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200168 (Универзитет у Београду, Хемијски факултет) (RS-MESTD-inst-2020-200168)
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200007 (Универзитет у Београду, Институт за биолошка истраживања 'Синиша Станковић') (RS-MESTD-inst-2020-200007)
Повезане информације:
- Друга верзија
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