TY  - JOUR
AU  - Andrić, Deana
AU  - Dukić-Stefanović, Slađana
AU  - Krunić, Mihajlo J.
AU  - Jevtić, Ivana I.
AU  - Penjišević, Jelena Z.
AU  - Šukalović, Vladimir B.
AU  - Kostić-Rajačić, Slađana
PY  - 2024
UR  - http://cherry.chem.bg.ac.rs/handle/123456789/6472
AB  - Serotonin, or 5-hydroxytryptamine (5-HT), is a biogenic amine most
noted as a neurotransmitter, an activator of the utmost subtype family of G-protein-
coupled receptors (GPCR). Drugs targeting 5-HT1A and other 5-HT receptors
treat central nervous system diseases such as schizophrenia and depression.
Recent advances in serotonin receptor structure research gave us several
crystal 5-HT1A receptor structures, most notably 5-HT1A bound to the antipsychotic
drug aripiprazole (Abilify®). This discovery prompted us to evaluate
a series of newly synthesized ligands for serotonergic activity since those arylpiperazine
derivatives share minimal general structure with aripiprazole. The
results of molecular docking analysis of unsubstituted starting substances
encouraged us to propound further modifications of the tail and head parts of
the parent molecules to maximize receptor binding affinity. Intrigued by the
results of molecular analysis, all foreseen derivatives were synthesized. The
pharmacological activity of all nine (5a and 6a are synthesized previously)
compounds was assessed by the in vitro tests and in silico pharmacokinetics
predictions for the most promising candidates. All tested ligands have improved
affinity compering to parent compounds (10a and 11a), 8b and 9b expressed
the best pharmacological profile with an improved binding affinity
toward serotonin 5-HT1A receptors (Ki 12.1 and 4.8 nM, respectively).
PB  - Belgrade : Serbian Chemical Society
T2  - J. Serb. Chem. Soc.
T1  - Synthesis, computational and pharmacological evaluation of novel N-{4-[2-(4-aryl-piperazin-1-yl)ethyl]phenyl}-arylamides
VL  - 89
IS  - 3
SP  - 291
EP  - 303
DO  - 10.2298/JSC230906076A
ER  - 

@article{
author = "Andrić, Deana and Dukić-Stefanović, Slađana and Krunić, Mihajlo J. and Jevtić, Ivana I. and Penjišević, Jelena Z. and Šukalović, Vladimir B. and Kostić-Rajačić, Slađana",
year = "2024",
abstract = "Serotonin, or 5-hydroxytryptamine (5-HT), is a biogenic amine most
noted as a neurotransmitter, an activator of the utmost subtype family of G-protein-
coupled receptors (GPCR). Drugs targeting 5-HT1A and other 5-HT receptors
treat central nervous system diseases such as schizophrenia and depression.
Recent advances in serotonin receptor structure research gave us several
crystal 5-HT1A receptor structures, most notably 5-HT1A bound to the antipsychotic
drug aripiprazole (Abilify®). This discovery prompted us to evaluate
a series of newly synthesized ligands for serotonergic activity since those arylpiperazine
derivatives share minimal general structure with aripiprazole. The
results of molecular docking analysis of unsubstituted starting substances
encouraged us to propound further modifications of the tail and head parts of
the parent molecules to maximize receptor binding affinity. Intrigued by the
results of molecular analysis, all foreseen derivatives were synthesized. The
pharmacological activity of all nine (5a and 6a are synthesized previously)
compounds was assessed by the in vitro tests and in silico pharmacokinetics
predictions for the most promising candidates. All tested ligands have improved
affinity compering to parent compounds (10a and 11a), 8b and 9b expressed
the best pharmacological profile with an improved binding affinity
toward serotonin 5-HT1A receptors (Ki 12.1 and 4.8 nM, respectively).",
publisher = "Belgrade : Serbian Chemical Society",
journal = "J. Serb. Chem. Soc.",
title = "Synthesis, computational and pharmacological evaluation of novel N-{4-[2-(4-aryl-piperazin-1-yl)ethyl]phenyl}-arylamides",
volume = "89",
number = "3",
pages = "291-303",
doi = "10.2298/JSC230906076A"
}

Andrić, D., Dukić-Stefanović, S., Krunić, M. J., Jevtić, I. I., Penjišević, J. Z., Šukalović, V. B.,& Kostić-Rajačić, S.. (2024). Synthesis, computational and pharmacological evaluation of novel N-{4-[2-(4-aryl-piperazin-1-yl)ethyl]phenyl}-arylamides. in J. Serb. Chem. Soc.
Belgrade : Serbian Chemical Society., 89(3), 291-303.
https://doi.org/10.2298/JSC230906076A

Andrić D, Dukić-Stefanović S, Krunić MJ, Jevtić II, Penjišević JZ, Šukalović VB, Kostić-Rajačić S. Synthesis, computational and pharmacological evaluation of novel N-{4-[2-(4-aryl-piperazin-1-yl)ethyl]phenyl}-arylamides. in J. Serb. Chem. Soc.. 2024;89(3):291-303.
doi:10.2298/JSC230906076A .

Andrić, Deana, Dukić-Stefanović, Slađana, Krunić, Mihajlo J., Jevtić, Ivana I., Penjišević, Jelena Z., Šukalović, Vladimir B., Kostić-Rajačić, Slađana, "Synthesis, computational and pharmacological evaluation of novel N-{4-[2-(4-aryl-piperazin-1-yl)ethyl]phenyl}-arylamides" in J. Serb. Chem. Soc., 89, no. 3 (2024):291-303,
https://doi.org/10.2298/JSC230906076A . .

TY  - JOUR
AU  - Šegan, Sandra B.
AU  - Krunić, Mihajlo J.
AU  - Andrić, Deana
AU  - Šukalović, Vladimir B.
AU  - Penjišević, Jelena Z.
AU  - Jevtić, Ivana I.
PY  - 2024
UR  - http://cherry.chem.bg.ac.rs/handle/123456789/6473
AB  - Fourteen donepezil-like acetylcholinesterase (AChE) inhibitors from our library were
analyzed using reversed-phase thin-layer chromatography to assess their lipophilicity
and blood–brain barrier permeability. Compounds possessed N-benzylpiperidine and
N,N-diarylpiperazine moieties connected via a short carboxamide or amine linker.
Retention parameters RM
0, b, and C0 were considered as the measures of lipophilicity.
Besides, logD of the investigated compounds was determined chromatographically
using standard compounds with known logPow and logD values at pH 11. Experimentally
obtained lipophilicity parameters correlated well with in silico generated results,
and the effect of the nature of the linker between two pharmacophores and
substituents on the arylpiperazine part of the molecule was observed. As a result of
drug-likeness analysis, both Lipinski's rule of five and Veber's rule parameters were
determined, suggesting that examined compounds could be potential candidates for
further drug development. Principal component analysis was performed to obtain an
insight into a grouping of compounds based on calculated structural descriptors,
experimentally obtained values of lipophilicity, and AChE inhibitory activity.
PB  - Wiley
T2  - Biomedical Chromatography
T1  - Evaluation of lipophilicity and drug-likeness of donepezil-like compounds using reversed-phase thin-layer chromatography
VL  - n/a
SP  - e5864
DO  - 10.1002/bmc.5867
ER  - 

@article{
author = "Šegan, Sandra B. and Krunić, Mihajlo J. and Andrić, Deana and Šukalović, Vladimir B. and Penjišević, Jelena Z. and Jevtić, Ivana I.",
year = "2024",
abstract = "Fourteen donepezil-like acetylcholinesterase (AChE) inhibitors from our library were
analyzed using reversed-phase thin-layer chromatography to assess their lipophilicity
and blood–brain barrier permeability. Compounds possessed N-benzylpiperidine and
N,N-diarylpiperazine moieties connected via a short carboxamide or amine linker.
Retention parameters RM
0, b, and C0 were considered as the measures of lipophilicity.
Besides, logD of the investigated compounds was determined chromatographically
using standard compounds with known logPow and logD values at pH 11. Experimentally
obtained lipophilicity parameters correlated well with in silico generated results,
and the effect of the nature of the linker between two pharmacophores and
substituents on the arylpiperazine part of the molecule was observed. As a result of
drug-likeness analysis, both Lipinski's rule of five and Veber's rule parameters were
determined, suggesting that examined compounds could be potential candidates for
further drug development. Principal component analysis was performed to obtain an
insight into a grouping of compounds based on calculated structural descriptors,
experimentally obtained values of lipophilicity, and AChE inhibitory activity.",
publisher = "Wiley",
journal = "Biomedical Chromatography",
title = "Evaluation of lipophilicity and drug-likeness of donepezil-like compounds using reversed-phase thin-layer chromatography",
volume = "n/a",
pages = "e5864",
doi = "10.1002/bmc.5867"
}

Šegan, S. B., Krunić, M. J., Andrić, D., Šukalović, V. B., Penjišević, J. Z.,& Jevtić, I. I.. (2024). Evaluation of lipophilicity and drug-likeness of donepezil-like compounds using reversed-phase thin-layer chromatography. in Biomedical Chromatography
Wiley., n/a, e5864.
https://doi.org/10.1002/bmc.5867

Šegan SB, Krunić MJ, Andrić D, Šukalović VB, Penjišević JZ, Jevtić II. Evaluation of lipophilicity and drug-likeness of donepezil-like compounds using reversed-phase thin-layer chromatography. in Biomedical Chromatography. 2024;n/a:e5864.
doi:10.1002/bmc.5867 .

Šegan, Sandra B., Krunić, Mihajlo J., Andrić, Deana, Šukalović, Vladimir B., Penjišević, Jelena Z., Jevtić, Ivana I., "Evaluation of lipophilicity and drug-likeness of donepezil-like compounds using reversed-phase thin-layer chromatography" in Biomedical Chromatography, n/a (2024):e5864,
https://doi.org/10.1002/bmc.5867 . .

TY  - 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 . .