Multi-target potential of newly designed tacrine-derived cholinesterase inhibitors: Synthesis, computational and pharmacological study
Samo za registrovane korisnike
2024
Autori
Jevtić, Ivana I.Suručić, Relja V.
Tovilović-Kovačević, Gordana
Zogović, Nevena
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Kostić-Rajačić, Sladjana V.
Andrić, Deana
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Penjišević, Jelena Z.
Članak u časopisu (Objavljena verzija)
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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.
Ključne reči:
Alzheimer’s disease / Tacrine / Piperidine-4-carboxamide / Cholinesterase / Cytotoxicity / Neuroprotection / Molecular docking / Molecular dynamics / ADMEIzvor:
Bioorganic & Medicinal Chemistry, 2024, 101, 117649-Izdavač:
- Elsevier
Finansiranje / projekti:
- Proučavanje odnosa strukture i aktivnosti novosintetisanih biološki aktivnih supstanci (RS-MESTD-Basic Research (BR or ON)-172032)
Kolekcije
Institucija/grupa
Hemijski fakultet / Faculty of ChemistryTY - JOUR AU - Jevtić, Ivana I. AU - Suručić, Relja V. AU - Tovilović-Kovačević, Gordana AU - Zogović, Nevena AU - Kostić-Rajačić, Sladjana V. AU - Andrić, Deana AU - Penjišević, Jelena Z. PY - 2024 UR - http://cherry.chem.bg.ac.rs/handle/123456789/6446 AB - 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. PB - Elsevier T2 - Bioorganic & Medicinal Chemistry T1 - Multi-target potential of newly designed tacrine-derived cholinesterase inhibitors: Synthesis, computational and pharmacological study VL - 101 SP - 117649 DO - 10.1016/j.bmc.2024.117649 ER -
@article{ author = "Jevtić, Ivana I. and Suručić, Relja V. and Tovilović-Kovačević, Gordana and Zogović, Nevena and Kostić-Rajačić, Sladjana V. and Andrić, Deana and Penjišević, Jelena Z.", year = "2024", abstract = "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.", publisher = "Elsevier", journal = "Bioorganic & Medicinal Chemistry", title = "Multi-target potential of newly designed tacrine-derived cholinesterase inhibitors: Synthesis, computational and pharmacological study", volume = "101", pages = "117649", doi = "10.1016/j.bmc.2024.117649" }
Jevtić, I. I., Suručić, R. V., Tovilović-Kovačević, G., Zogović, N., Kostić-Rajačić, S. V., Andrić, D.,& Penjišević, J. Z.. (2024). Multi-target potential of newly designed tacrine-derived cholinesterase inhibitors: Synthesis, computational and pharmacological study. in Bioorganic & Medicinal Chemistry Elsevier., 101, 117649. https://doi.org/10.1016/j.bmc.2024.117649
Jevtić II, Suručić RV, Tovilović-Kovačević G, Zogović N, Kostić-Rajačić SV, Andrić D, Penjišević JZ. Multi-target potential of newly designed tacrine-derived cholinesterase inhibitors: Synthesis, computational and pharmacological study. in Bioorganic & Medicinal Chemistry. 2024;101:117649. doi:10.1016/j.bmc.2024.117649 .
Jevtić, Ivana I., Suručić, Relja V., Tovilović-Kovačević, Gordana, Zogović, Nevena, Kostić-Rajačić, Sladjana V., Andrić, Deana, Penjišević, Jelena Z., "Multi-target potential of newly designed tacrine-derived cholinesterase inhibitors: Synthesis, computational and pharmacological study" in Bioorganic & Medicinal Chemistry, 101 (2024):117649, https://doi.org/10.1016/j.bmc.2024.117649 . .