TY  - JOUR
AU  - Bagán, Andrea
AU  - Rodriguez-Arévalo, Sergio
AU  - Taboada-Jara, Teresa
AU  - Griñán-Ferré, Christian
AU  - Pallàs, Mercè
AU  - Brocos-Mosquera, Iria
AU  - Callado, Luis F.
AU  - Morales-García, José A.
AU  - Pérez, Belén
AU  - Diaz, Caridad
AU  - Fernández-Godino, Rosario
AU  - Genilloud, Olga
AU  - Beljkaš, Milan
AU  - Oljačić, Slavica
AU  - Nikolić, Katarina
AU  - Escolano, Carmen
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5206
AB  - Humanity is facing a vast prevalence of neurodegenerative diseases, with Alzheimer’s disease (AD) being the most dominant, without efficacious drugs, and with only a few therapeutic targets identified. In this scenario, we aim to find molecular entities that modulate imidazoline I2 receptors (I2-IRs) that have been pointed out as relevant targets in AD. In this work, we explored structural modifications of well-established I2-IR ligands, giving access to derivatives with an imidazole-linked heterocycle as a common key feature. We report the synthesis, the affinity in human I2-IRs, the brain penetration capabilities, the in silico ADMET studies, and the three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of this new bunch of I2-IR ligands. Selected compounds showed neuroprotective properties and beneficial effects in an in vitro model of Parkinson’s disease, rescued the human dopaminergic cell line SH-SY5Y from death after treatment with 6-hydroxydopamine, and showed crucial anti-inflammatory effects in a cellular model of neuroinflammation. After a preliminary pharmacokinetic study, we explored the action of our representative 2-(benzo[b]thiophen-2-yl)-1H-imidazole LSL33 in a mouse model of AD (5xFAD). Oral administration of LSL33 at 2 mg/Kg for 4 weeks ameliorated 5XFAD cognitive impairment and synaptic plasticity, as well as reduced neuroinflammation markers. In summary, this new I2-IR ligand that promoted beneficial effects in a well-established AD mouse model should be considered a promising therapeutic strategy for neurodegeneration.
PB  - MDPI
T2  - Pharmaceutics
T1  - Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease
VL  - 15
IS  - 10
DO  - 10.3390/pharmaceutics15102381
ER  - 

@article{
author = "Bagán, Andrea and Rodriguez-Arévalo, Sergio and Taboada-Jara, Teresa and Griñán-Ferré, Christian and Pallàs, Mercè and Brocos-Mosquera, Iria and Callado, Luis F. and Morales-García, José A. and Pérez, Belén and Diaz, Caridad and Fernández-Godino, Rosario and Genilloud, Olga and Beljkaš, Milan and Oljačić, Slavica and Nikolić, Katarina and Escolano, Carmen",
year = "2023",
abstract = "Humanity is facing a vast prevalence of neurodegenerative diseases, with Alzheimer’s disease (AD) being the most dominant, without efficacious drugs, and with only a few therapeutic targets identified. In this scenario, we aim to find molecular entities that modulate imidazoline I2 receptors (I2-IRs) that have been pointed out as relevant targets in AD. In this work, we explored structural modifications of well-established I2-IR ligands, giving access to derivatives with an imidazole-linked heterocycle as a common key feature. We report the synthesis, the affinity in human I2-IRs, the brain penetration capabilities, the in silico ADMET studies, and the three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of this new bunch of I2-IR ligands. Selected compounds showed neuroprotective properties and beneficial effects in an in vitro model of Parkinson’s disease, rescued the human dopaminergic cell line SH-SY5Y from death after treatment with 6-hydroxydopamine, and showed crucial anti-inflammatory effects in a cellular model of neuroinflammation. After a preliminary pharmacokinetic study, we explored the action of our representative 2-(benzo[b]thiophen-2-yl)-1H-imidazole LSL33 in a mouse model of AD (5xFAD). Oral administration of LSL33 at 2 mg/Kg for 4 weeks ameliorated 5XFAD cognitive impairment and synaptic plasticity, as well as reduced neuroinflammation markers. In summary, this new I2-IR ligand that promoted beneficial effects in a well-established AD mouse model should be considered a promising therapeutic strategy for neurodegeneration.",
publisher = "MDPI",
journal = "Pharmaceutics",
title = "Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease",
volume = "15",
number = "10",
doi = "10.3390/pharmaceutics15102381"
}

Bagán, A., Rodriguez-Arévalo, S., Taboada-Jara, T., Griñán-Ferré, C., Pallàs, M., Brocos-Mosquera, I., Callado, L. F., Morales-García, J. A., Pérez, B., Diaz, C., Fernández-Godino, R., Genilloud, O., Beljkaš, M., Oljačić, S., Nikolić, K.,& Escolano, C.. (2023). Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease. in Pharmaceutics
MDPI., 15(10).
https://doi.org/10.3390/pharmaceutics15102381

Bagán A, Rodriguez-Arévalo S, Taboada-Jara T, Griñán-Ferré C, Pallàs M, Brocos-Mosquera I, Callado LF, Morales-García JA, Pérez B, Diaz C, Fernández-Godino R, Genilloud O, Beljkaš M, Oljačić S, Nikolić K, Escolano C. Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease. in Pharmaceutics. 2023;15(10).
doi:10.3390/pharmaceutics15102381 .

Bagán, Andrea, Rodriguez-Arévalo, Sergio, Taboada-Jara, Teresa, Griñán-Ferré, Christian, Pallàs, Mercè, Brocos-Mosquera, Iria, Callado, Luis F., Morales-García, José A., Pérez, Belén, Diaz, Caridad, Fernández-Godino, Rosario, Genilloud, Olga, Beljkaš, Milan, Oljačić, Slavica, Nikolić, Katarina, Escolano, Carmen, "Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease" in Pharmaceutics, 15, no. 10 (2023),
https://doi.org/10.3390/pharmaceutics15102381 . .

TY  - JOUR
AU  - Madžgalj, Valerija
AU  - Petrović, Aleksandar
AU  - Čakar, Uroš
AU  - Maraš, Vesna
AU  - Sofrenić, Ivana
AU  - Tešević, Vele
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4428
AB  - This study aimed to show aromatic profile of wines produced from two autochthonous grape cultivars Krstač (K) and Žižak (Z). During the wine production two enzymatic preparations (EP) Lallzyme cuvee blanc (CB) and Lallzyme enzymatic preparation β (EB) and different time of skin contact (4 and 8 h) were applied. Aromatic compounds were detected by GC/FID–MS analysis. Significantly higher content of total detected aromatic compounds compared to appropriate controls (168.54 and 161.72 mg L-1 ) was observed for K EB4h (176.33 mg L -1 ) and Z CB4h (177.29 mg L -1 ) wines. Skin contact and usage of EP mostly increased content of 2-phenylethyl and isoamyl alcohols. Wines from both varieties showed higher content of hexanoic and octanoic acids compared to the control. It is interesting to emphasize that content of esters that are responsible for fruity aroma of wine which is important for plea- sant taste (isoamyl acetate – banana, ethyl hexanoate – ripe banana, 2-phenyl- ethyl acetate – powerful fruity rose like) were increased in all samples com- pared to the controls. The highest grades, after sensory evaluation, were obtained for K EB 8h (18.0 out of 20.0) and Z CB 8h (18.2 out of 20.0).
AB  - Ова студија је имала за циљ да прикаже профиле ароматичних једињења вина про- изведених од аутохтоних сорти грожђа Крстач (K) и Жижак (Z). Током производње вина од обе сорте коришћени су ензимски препарати (EP): Lallzyme cuvee blanc (CB), Lall- zyme enzymatic preparation β (EB) и различито време контакта покожице (4 и 8 h). Аро- матична једињења су анализирана GC/FID–MS техником. За вина K ЕВ4h (176,33 mg L -1 ) и Z CB4h (177,29 mg L -1 ) уочава се значајно већи садржај укупних ароматичних једињења у поређењу са одговарајућим контролним винима (168,54 and 161,72 mg L -1 ). Про- дужење времена контакта покожице и употреба ЕP углавном повећава садржај 2-фенил- етил- и изоамил-алкохола. Вина обе сорте су показала већи садржај хексанске и октан- ске киселине у односу на контролна вина. Занимљиво је поменути да је у свим узорцима повећан садржај естара који су одговорни за воћну арому вина, која је заслужна за при- јатан укус (изоамил-ацетат – банана, етил-хексаноат – зрела банана, 2-фенилетил-аце- тат – јак воћни мирис руже), у поређењу са контролним винима. Највише оцене, након сензорног оцењивања, добијене су за K EB 8h (18,0 од максималних 20,0) и Z CB 8h (18,2 од максималних 20,0).
PB  - Serbian Chemical Society
T2  - Journal of the Serbian Chemical Society
T1  - The influence of different enzymatic preparations and skin contact time on aromatic profile of wines produced from autochthonous grape varieties Krstac and Zizak
T1  - Утицај различитих ензимских третмана и времена контакта покожице на ароматске профиле вина произведених од аутохтоних сорти грожђа Крстач и Жижак
VL  - 88
IS  - 1
SP  - 11
EP  - 23
DO  - 10.2298/JSC220311056M
ER  - 

@article{
author = "Madžgalj, Valerija and Petrović, Aleksandar and Čakar, Uroš and Maraš, Vesna and Sofrenić, Ivana and Tešević, Vele",
year = "2023",
abstract = "This study aimed to show aromatic profile of wines produced from two autochthonous grape cultivars Krstač (K) and Žižak (Z). During the wine production two enzymatic preparations (EP) Lallzyme cuvee blanc (CB) and Lallzyme enzymatic preparation β (EB) and different time of skin contact (4 and 8 h) were applied. Aromatic compounds were detected by GC/FID–MS analysis. Significantly higher content of total detected aromatic compounds compared to appropriate controls (168.54 and 161.72 mg L-1 ) was observed for K EB4h (176.33 mg L -1 ) and Z CB4h (177.29 mg L -1 ) wines. Skin contact and usage of EP mostly increased content of 2-phenylethyl and isoamyl alcohols. Wines from both varieties showed higher content of hexanoic and octanoic acids compared to the control. It is interesting to emphasize that content of esters that are responsible for fruity aroma of wine which is important for plea- sant taste (isoamyl acetate – banana, ethyl hexanoate – ripe banana, 2-phenyl- ethyl acetate – powerful fruity rose like) were increased in all samples com- pared to the controls. The highest grades, after sensory evaluation, were obtained for K EB 8h (18.0 out of 20.0) and Z CB 8h (18.2 out of 20.0)., Ова студија је имала за циљ да прикаже профиле ароматичних једињења вина про- изведених од аутохтоних сорти грожђа Крстач (K) и Жижак (Z). Током производње вина од обе сорте коришћени су ензимски препарати (EP): Lallzyme cuvee blanc (CB), Lall- zyme enzymatic preparation β (EB) и различито време контакта покожице (4 и 8 h). Аро- матична једињења су анализирана GC/FID–MS техником. За вина K ЕВ4h (176,33 mg L -1 ) и Z CB4h (177,29 mg L -1 ) уочава се значајно већи садржај укупних ароматичних једињења у поређењу са одговарајућим контролним винима (168,54 and 161,72 mg L -1 ). Про- дужење времена контакта покожице и употреба ЕP углавном повећава садржај 2-фенил- етил- и изоамил-алкохола. Вина обе сорте су показала већи садржај хексанске и октан- ске киселине у односу на контролна вина. Занимљиво је поменути да је у свим узорцима повећан садржај естара који су одговорни за воћну арому вина, која је заслужна за при- јатан укус (изоамил-ацетат – банана, етил-хексаноат – зрела банана, 2-фенилетил-аце- тат – јак воћни мирис руже), у поређењу са контролним винима. Највише оцене, након сензорног оцењивања, добијене су за K EB 8h (18,0 од максималних 20,0) и Z CB 8h (18,2 од максималних 20,0).",
publisher = "Serbian Chemical Society",
journal = "Journal of the Serbian Chemical Society",
title = "The influence of different enzymatic preparations and skin contact time on aromatic profile of wines produced from autochthonous grape varieties Krstac and Zizak, Утицај различитих ензимских третмана и времена контакта покожице на ароматске профиле вина произведених од аутохтоних сорти грожђа Крстач и Жижак",
volume = "88",
number = "1",
pages = "11-23",
doi = "10.2298/JSC220311056M"
}

Madžgalj, V., Petrović, A., Čakar, U., Maraš, V., Sofrenić, I.,& Tešević, V.. (2023). The influence of different enzymatic preparations and skin contact time on aromatic profile of wines produced from autochthonous grape varieties Krstac and Zizak. in Journal of the Serbian Chemical Society
Serbian Chemical Society., 88(1), 11-23.
https://doi.org/10.2298/JSC220311056M

Madžgalj V, Petrović A, Čakar U, Maraš V, Sofrenić I, Tešević V. The influence of different enzymatic preparations and skin contact time on aromatic profile of wines produced from autochthonous grape varieties Krstac and Zizak. in Journal of the Serbian Chemical Society. 2023;88(1):11-23.
doi:10.2298/JSC220311056M .

Madžgalj, Valerija, Petrović, Aleksandar, Čakar, Uroš, Maraš, Vesna, Sofrenić, Ivana, Tešević, Vele, "The influence of different enzymatic preparations and skin contact time on aromatic profile of wines produced from autochthonous grape varieties Krstac and Zizak" in Journal of the Serbian Chemical Society, 88, no. 1 (2023):11-23,
https://doi.org/10.2298/JSC220311056M . .

TY  - JOUR
AU  - Krmar, Jovana
AU  - Tolić Stojadinović, Ljiljana
AU  - Đurkić, Tatjana
AU  - Protić, Ana
AU  - Otašević, Biljana
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4881
AB  - A priori estimation of analyte response is crucial for the efficient development of liquid chromatography–electrospray ionization/mass spectrometry (LC–ESI/MS) methods, but remains a demanding task given the lack of knowledge about the factors affecting the experimental outcome. In this research, we address the challenge of discovering the interactive relationship between signal response and structural properties, method parameters and solvent-related descriptors throughout an approach featuring quantitative structure–property relationship (QSPR) and design of experiments (DoE). To systematically investigate the experimental domain within which QSPR prediction should be undertaken, we varied LC and instrumental factors according to the Box-Behnken DoE scheme. Seven compounds, including aripiprazole and its impurities, were subjected to 57 different experimental conditions, resulting in 399 LC–ESI/MS data endpoints. To obtain a more standard distribution of the measured response, the peak areas were log-transformed before modeling. QSPR predictions were made using features selected by Genetic Algorithm (GA) and providing Gradient Boosted Trees (GBT) with training data. Proposed model showed satisfactory performance on test data with a RMSEP of 1.57 % and a of 96.48 %. This is the first QSPR study in LC–ESI/MS that provided a holistic overview of the analyte’s response behavior across the experimental and chemical space. Since intramolecular electronic effects and molecular size were given great importance, the GA–GBT model improved the understanding of signal response generation of model compounds. It also highlighted the need to fine-tune the parameters affecting desolvation and droplet charging efficiency.
PB  - Elsevier Inc.
T2  - Journal of Pharmaceutical and Biomedical Analysis
T1  - Predicting liquid chromatography−electrospray ionization/mass spectrometry signal from the structure of model compounds and experimental factors; case study of aripiprazole and its impurities
VL  - 233
DO  - 10.1016/j.jpba.2023.115422
ER  - 

@article{
author = "Krmar, Jovana and Tolić Stojadinović, Ljiljana and Đurkić, Tatjana and Protić, Ana and Otašević, Biljana",
year = "2023",
abstract = "A priori estimation of analyte response is crucial for the efficient development of liquid chromatography–electrospray ionization/mass spectrometry (LC–ESI/MS) methods, but remains a demanding task given the lack of knowledge about the factors affecting the experimental outcome. In this research, we address the challenge of discovering the interactive relationship between signal response and structural properties, method parameters and solvent-related descriptors throughout an approach featuring quantitative structure–property relationship (QSPR) and design of experiments (DoE). To systematically investigate the experimental domain within which QSPR prediction should be undertaken, we varied LC and instrumental factors according to the Box-Behnken DoE scheme. Seven compounds, including aripiprazole and its impurities, were subjected to 57 different experimental conditions, resulting in 399 LC–ESI/MS data endpoints. To obtain a more standard distribution of the measured response, the peak areas were log-transformed before modeling. QSPR predictions were made using features selected by Genetic Algorithm (GA) and providing Gradient Boosted Trees (GBT) with training data. Proposed model showed satisfactory performance on test data with a RMSEP of 1.57 % and a of 96.48 %. This is the first QSPR study in LC–ESI/MS that provided a holistic overview of the analyte’s response behavior across the experimental and chemical space. Since intramolecular electronic effects and molecular size were given great importance, the GA–GBT model improved the understanding of signal response generation of model compounds. It also highlighted the need to fine-tune the parameters affecting desolvation and droplet charging efficiency.",
publisher = "Elsevier Inc.",
journal = "Journal of Pharmaceutical and Biomedical Analysis",
title = "Predicting liquid chromatography−electrospray ionization/mass spectrometry signal from the structure of model compounds and experimental factors; case study of aripiprazole and its impurities",
volume = "233",
doi = "10.1016/j.jpba.2023.115422"
}

Krmar, J., Tolić Stojadinović, L., Đurkić, T., Protić, A.,& Otašević, B.. (2023). Predicting liquid chromatography−electrospray ionization/mass spectrometry signal from the structure of model compounds and experimental factors; case study of aripiprazole and its impurities. in Journal of Pharmaceutical and Biomedical Analysis
Elsevier Inc.., 233.
https://doi.org/10.1016/j.jpba.2023.115422

Krmar J, Tolić Stojadinović L, Đurkić T, Protić A, Otašević B. Predicting liquid chromatography−electrospray ionization/mass spectrometry signal from the structure of model compounds and experimental factors; case study of aripiprazole and its impurities. in Journal of Pharmaceutical and Biomedical Analysis. 2023;233.
doi:10.1016/j.jpba.2023.115422 .

Krmar, Jovana, Tolić Stojadinović, Ljiljana, Đurkić, Tatjana, Protić, Ana, Otašević, Biljana, "Predicting liquid chromatography−electrospray ionization/mass spectrometry signal from the structure of model compounds and experimental factors; case study of aripiprazole and its impurities" in Journal of Pharmaceutical and Biomedical Analysis, 233 (2023),
https://doi.org/10.1016/j.jpba.2023.115422 . .

TY  - JOUR
AU  - Divović-Matović, Branka
AU  - Knutson, Dan
AU  - Mitrović, Jelena
AU  - Stevanović, Vladimir
AU  - Stanojević, Boban
AU  - Savić, Snežana
AU  - Cook, James
AU  - Savić, Miroslav
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4289
AB  - Several pyrazoloquinolinone (PQ) ligands were recently discovered as func-tionally selective positive modulators at the PQ site ofα6-containing GABAAreceptors. PQs are also neutral modulators at the benzodiazepine site. Weassessed the influence of PQ compounds from three structural groups (PZ-II-029 and related deuterated analogues DK-I-56-1, RV-I-029, DK-I-60-3 and DK-I-86-1; LAU 463 and related analogues DK-I-58-1 and DK-II-58-1; and DK-I-87-1), alone and in combination with diazepam, on the behaviour of maleSprague–Dawley rats. An excellent behavioural safety profile of all tested PQswas demonstrated in the spontaneous locomotor activity, rotarod, loss of right-ing reflex and pentylenetetrazol tests. In interaction studies, only PZ-II-029and its analogues prevented the ataxic effects of the benzodiazepine, asassessed in the rotarod test and during monitoring of rat locomotor activityafter awakening from the loss of righting reflex. Published electrophysiologicalprofiles of PQ ligands imply that positive modulation elicited atα6-GABAAreceptors that contain theγ2 andδsubunit, rather than their neutral modula-tory action at the benzodiazepine site, may prevent the ataxic action of diaze-pam. Thus, PZ-II-029 and its deuterated analogues are not prone to untowardinteractions with benzodiazepines and may indeed completely abolish theirataxic action, seen at therapeutic, and especially toxic concentrations.
PB  - John Wiley and Sons Inc
T2  - Basic and Clinical Pharmacology and Toxicology
T1  - Behavioural interaction of pyrazoloquinolinone positive allosteric modulators at α6GABAA receptors and diazepam in rats: Anti-diazepam-induced ataxia action as a structure-dependent feature
VL  - 131
IS  - 6
SP  - 514
EP  - 524
DO  - 10.1111/bcpt.13801
ER  - 

@article{
author = "Divović-Matović, Branka and Knutson, Dan and Mitrović, Jelena and Stevanović, Vladimir and Stanojević, Boban and Savić, Snežana and Cook, James and Savić, Miroslav",
year = "2022",
abstract = "Several pyrazoloquinolinone (PQ) ligands were recently discovered as func-tionally selective positive modulators at the PQ site ofα6-containing GABAAreceptors. PQs are also neutral modulators at the benzodiazepine site. Weassessed the influence of PQ compounds from three structural groups (PZ-II-029 and related deuterated analogues DK-I-56-1, RV-I-029, DK-I-60-3 and DK-I-86-1; LAU 463 and related analogues DK-I-58-1 and DK-II-58-1; and DK-I-87-1), alone and in combination with diazepam, on the behaviour of maleSprague–Dawley rats. An excellent behavioural safety profile of all tested PQswas demonstrated in the spontaneous locomotor activity, rotarod, loss of right-ing reflex and pentylenetetrazol tests. In interaction studies, only PZ-II-029and its analogues prevented the ataxic effects of the benzodiazepine, asassessed in the rotarod test and during monitoring of rat locomotor activityafter awakening from the loss of righting reflex. Published electrophysiologicalprofiles of PQ ligands imply that positive modulation elicited atα6-GABAAreceptors that contain theγ2 andδsubunit, rather than their neutral modula-tory action at the benzodiazepine site, may prevent the ataxic action of diaze-pam. Thus, PZ-II-029 and its deuterated analogues are not prone to untowardinteractions with benzodiazepines and may indeed completely abolish theirataxic action, seen at therapeutic, and especially toxic concentrations.",
publisher = "John Wiley and Sons Inc",
journal = "Basic and Clinical Pharmacology and Toxicology",
title = "Behavioural interaction of pyrazoloquinolinone positive allosteric modulators at α6GABAA receptors and diazepam in rats: Anti-diazepam-induced ataxia action as a structure-dependent feature",
volume = "131",
number = "6",
pages = "514-524",
doi = "10.1111/bcpt.13801"
}

Divović-Matović, B., Knutson, D., Mitrović, J., Stevanović, V., Stanojević, B., Savić, S., Cook, J.,& Savić, M.. (2022). Behavioural interaction of pyrazoloquinolinone positive allosteric modulators at α6GABAA receptors and diazepam in rats: Anti-diazepam-induced ataxia action as a structure-dependent feature. in Basic and Clinical Pharmacology and Toxicology
John Wiley and Sons Inc., 131(6), 514-524.
https://doi.org/10.1111/bcpt.13801

Divović-Matović B, Knutson D, Mitrović J, Stevanović V, Stanojević B, Savić S, Cook J, Savić M. Behavioural interaction of pyrazoloquinolinone positive allosteric modulators at α6GABAA receptors and diazepam in rats: Anti-diazepam-induced ataxia action as a structure-dependent feature. in Basic and Clinical Pharmacology and Toxicology. 2022;131(6):514-524.
doi:10.1111/bcpt.13801 .

Divović-Matović, Branka, Knutson, Dan, Mitrović, Jelena, Stevanović, Vladimir, Stanojević, Boban, Savić, Snežana, Cook, James, Savić, Miroslav, "Behavioural interaction of pyrazoloquinolinone positive allosteric modulators at α6GABAA receptors and diazepam in rats: Anti-diazepam-induced ataxia action as a structure-dependent feature" in Basic and Clinical Pharmacology and Toxicology, 131, no. 6 (2022):514-524,
https://doi.org/10.1111/bcpt.13801 . .

TY  - JOUR
AU  - Ružić, Dušan
AU  - Ellinger, Bernhard
AU  - Đoković, Nemanja
AU  - Santibanez, Juan
AU  - Gul, Sheraz
AU  - Beljkaš, Milan
AU  - Đurić, Ana
AU  - Ganesan, Arasu
AU  - Pavić, Aleksandar
AU  - Srdić-Rajić, Tatjana
AU  - Petković, Miloš
AU  - Nikolić, Katarina
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4368
AB  - Isoform-selective histone deacetylase (HDAC) inhibition is promoted as a rational strategy to develop safer anti-cancer drugs compared to non-selective HDAC inhibitors. Despite this presumed benefit, considerably more non-selective HDAC inhibitors have undergone clinical trials. In this report, we detail the design and discovery of potent HDAC inhibitors, with 1-benzhydryl piperazine as a surface recognition group, that differ in hydrocarbon linker. In vitro HDAC screening identified two selective HDAC6 inhibitors with nanomolar IC50 values, as well as two non-selective nanomolar HDAC inhibitors. Structure-based molecular modeling was employed to study the influence of linker chemistry of synthesized inhibitors on HDAC6 potency. The breast cancer cell lines (MDA-MB-231 and MCF-7) were used to evaluate compound-mediated in vitro anti-cancer, anti-migratory, and anti-invasive activities. Experiments on the zebrafish MDA-MB-231 xenograft model revealed that a novel non-selective HDAC inhibitor with a seven-carbon-atom linker exhibits potent anti-tumor, anti-metastatic, and anti-angiogenic effects when tested at low micromolar concentrations.
PB  - MDPI
T2  - Pharmaceutics
T1  - Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation
VL  - 14
IS  - 12
DO  - 10.3390/pharmaceutics14122600
ER  - 

@article{
author = "Ružić, Dušan and Ellinger, Bernhard and Đoković, Nemanja and Santibanez, Juan and Gul, Sheraz and Beljkaš, Milan and Đurić, Ana and Ganesan, Arasu and Pavić, Aleksandar and Srdić-Rajić, Tatjana and Petković, Miloš and Nikolić, Katarina",
year = "2022",
abstract = "Isoform-selective histone deacetylase (HDAC) inhibition is promoted as a rational strategy to develop safer anti-cancer drugs compared to non-selective HDAC inhibitors. Despite this presumed benefit, considerably more non-selective HDAC inhibitors have undergone clinical trials. In this report, we detail the design and discovery of potent HDAC inhibitors, with 1-benzhydryl piperazine as a surface recognition group, that differ in hydrocarbon linker. In vitro HDAC screening identified two selective HDAC6 inhibitors with nanomolar IC50 values, as well as two non-selective nanomolar HDAC inhibitors. Structure-based molecular modeling was employed to study the influence of linker chemistry of synthesized inhibitors on HDAC6 potency. The breast cancer cell lines (MDA-MB-231 and MCF-7) were used to evaluate compound-mediated in vitro anti-cancer, anti-migratory, and anti-invasive activities. Experiments on the zebrafish MDA-MB-231 xenograft model revealed that a novel non-selective HDAC inhibitor with a seven-carbon-atom linker exhibits potent anti-tumor, anti-metastatic, and anti-angiogenic effects when tested at low micromolar concentrations.",
publisher = "MDPI",
journal = "Pharmaceutics",
title = "Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation",
volume = "14",
number = "12",
doi = "10.3390/pharmaceutics14122600"
}

Ružić, D., Ellinger, B., Đoković, N., Santibanez, J., Gul, S., Beljkaš, M., Đurić, A., Ganesan, A., Pavić, A., Srdić-Rajić, T., Petković, M.,& Nikolić, K.. (2022). Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation. in Pharmaceutics
MDPI., 14(12).
https://doi.org/10.3390/pharmaceutics14122600

Ružić D, Ellinger B, Đoković N, Santibanez J, Gul S, Beljkaš M, Đurić A, Ganesan A, Pavić A, Srdić-Rajić T, Petković M, Nikolić K. Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation. in Pharmaceutics. 2022;14(12).
doi:10.3390/pharmaceutics14122600 .

Ružić, Dušan, Ellinger, Bernhard, Đoković, Nemanja, Santibanez, Juan, Gul, Sheraz, Beljkaš, Milan, Đurić, Ana, Ganesan, Arasu, Pavić, Aleksandar, Srdić-Rajić, Tatjana, Petković, Miloš, Nikolić, Katarina, "Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation" in Pharmaceutics, 14, no. 12 (2022),
https://doi.org/10.3390/pharmaceutics14122600 . .

TY  - JOUR
AU  - Jovanović, Marija
AU  - Vučićević, Katarina
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4303
AB  - Optimizing the dosing of medicines for pediatric patients in routine clinical practice and determining the dose for clinical trials is still a challenging task. Children differ from adults in their response to drugs due to inherent differences in pharmacokinetics and/or pharmacodynamics, and responses may also vary among pediatric patients of different ages. However, the greatest disparities compared to adult pharmacokinetic profiles are observed in children below 2 years of age. The maturation of the liver and the kidneys, as well as the variation in body composition, are considered to be the main sources of pharmacokinetic variability. Hence, besides specific pharmacodynamic features, understanding age-related changes in drug absorption, distribution, and elimination is fundamental for optimizing drug efficacy and avoiding toxicity. This paper summarizes the pharmacokinetic changes throughout the childhood, along with the effect of developmental changes on drug dosage calculation. In clinical practice, age and body weight-based dosing regimens are usually used. In spite of dosing recommendations based on age and/or body weight, variabilities in pharmacokinetics and pharmacodynamic response remain, implying a need to monitor patients and optimize the dosing regimen according to physiological characteristics, disease characteristics and therapy.
AB  - Optimizacija doziranja lekova kod pedijatrijskih pacijenata u rutinskoj kliničkoj praksi i procena doze pre započinjanja kliničkih studija je i dalje značajan izazov. Pedijatrijska populacija se razlikuje od odraslih pacijenata u odgovoru na lekove, što je uzrokovano izmenjenom farmakokinetikom i/ili farmakodinamikom, a odgovor može varirati i među decom različitog uzrasta. Međutim, najveće razlike u odnosu na farmakokinetičke profile odraslih pacijenata primećuju se kod dece mlađe od 2 godine. Sazrevanje jetre i bubrega, kao i promene u udelu telesnih tečenosti i masnog tkiva u odnosu na ukupnu telesnu masu, smatraju se glavnim izvorima farmakokinetičke varijabilnosti. Dakle, pored specifičnih farmakodinamičkih karakteristika, razumevanje razvojnih promena u resorpciji, raspodeli i eliminaciji leka je fundamentalno za optimizaciju efikasnosti i bezbednosti terapije. Ovaj rad sumira farmakokinetičke promene tokom detinjstva, zajedno sa uticajem razvojnih promena na izračunavanje doze leka. U kliničkoj praksi se obično koriste režimi doziranja zasnovani na starosti i telesnoj masi. Uprkos preporukama za doziranje na osnovu godina i/ili telesne mase, i dalje se uočava varijabilnost u farmakokinetici i farmakodinamičkom odgovoru, što ukazuje na potrebu za praćenjem pacijenata i optimizacijom režima doziranja prema fiziološkim karakteristikama, karakteristikama bolesti i terapiji.
PB  - Pharmaceutical Association of Serbia
T2  - Arhiv za farmaciju
T1  - Pediatric pharmacokinetic considerations and implications for drug dosing
T1  - Značaj farmakokinetike u doziranju lekova kod pedijatrijskih pacijenata
VL  - 72
IS  - 3
SP  - 340
EP  - 352
DO  - 10.5937/arhfarm72-37605
ER  - 

@article{
author = "Jovanović, Marija and Vučićević, Katarina",
year = "2022",
abstract = "Optimizing the dosing of medicines for pediatric patients in routine clinical practice and determining the dose for clinical trials is still a challenging task. Children differ from adults in their response to drugs due to inherent differences in pharmacokinetics and/or pharmacodynamics, and responses may also vary among pediatric patients of different ages. However, the greatest disparities compared to adult pharmacokinetic profiles are observed in children below 2 years of age. The maturation of the liver and the kidneys, as well as the variation in body composition, are considered to be the main sources of pharmacokinetic variability. Hence, besides specific pharmacodynamic features, understanding age-related changes in drug absorption, distribution, and elimination is fundamental for optimizing drug efficacy and avoiding toxicity. This paper summarizes the pharmacokinetic changes throughout the childhood, along with the effect of developmental changes on drug dosage calculation. In clinical practice, age and body weight-based dosing regimens are usually used. In spite of dosing recommendations based on age and/or body weight, variabilities in pharmacokinetics and pharmacodynamic response remain, implying a need to monitor patients and optimize the dosing regimen according to physiological characteristics, disease characteristics and therapy., Optimizacija doziranja lekova kod pedijatrijskih pacijenata u rutinskoj kliničkoj praksi i procena doze pre započinjanja kliničkih studija je i dalje značajan izazov. Pedijatrijska populacija se razlikuje od odraslih pacijenata u odgovoru na lekove, što je uzrokovano izmenjenom farmakokinetikom i/ili farmakodinamikom, a odgovor može varirati i među decom različitog uzrasta. Međutim, najveće razlike u odnosu na farmakokinetičke profile odraslih pacijenata primećuju se kod dece mlađe od 2 godine. Sazrevanje jetre i bubrega, kao i promene u udelu telesnih tečenosti i masnog tkiva u odnosu na ukupnu telesnu masu, smatraju se glavnim izvorima farmakokinetičke varijabilnosti. Dakle, pored specifičnih farmakodinamičkih karakteristika, razumevanje razvojnih promena u resorpciji, raspodeli i eliminaciji leka je fundamentalno za optimizaciju efikasnosti i bezbednosti terapije. Ovaj rad sumira farmakokinetičke promene tokom detinjstva, zajedno sa uticajem razvojnih promena na izračunavanje doze leka. U kliničkoj praksi se obično koriste režimi doziranja zasnovani na starosti i telesnoj masi. Uprkos preporukama za doziranje na osnovu godina i/ili telesne mase, i dalje se uočava varijabilnost u farmakokinetici i farmakodinamičkom odgovoru, što ukazuje na potrebu za praćenjem pacijenata i optimizacijom režima doziranja prema fiziološkim karakteristikama, karakteristikama bolesti i terapiji.",
publisher = "Pharmaceutical Association of Serbia",
journal = "Arhiv za farmaciju",
title = "Pediatric pharmacokinetic considerations and implications for drug dosing, Značaj farmakokinetike u doziranju lekova kod pedijatrijskih pacijenata",
volume = "72",
number = "3",
pages = "340-352",
doi = "10.5937/arhfarm72-37605"
}

Jovanović, M.,& Vučićević, K.. (2022). Pediatric pharmacokinetic considerations and implications for drug dosing. in Arhiv za farmaciju
Pharmaceutical Association of Serbia., 72(3), 340-352.
https://doi.org/10.5937/arhfarm72-37605

Jovanović M, Vučićević K. Pediatric pharmacokinetic considerations and implications for drug dosing. in Arhiv za farmaciju. 2022;72(3):340-352.
doi:10.5937/arhfarm72-37605 .

Jovanović, Marija, Vučićević, Katarina, "Pediatric pharmacokinetic considerations and implications for drug dosing" in Arhiv za farmaciju, 72, no. 3 (2022):340-352,
https://doi.org/10.5937/arhfarm72-37605 . .

TY  - JOUR
AU  - Simić, Milena
AU  - Erić, Slavica
AU  - Borić, Ivan
AU  - Lubelska, Annamaria
AU  - Latacz, Gneiwomir
AU  - Kiec-Kononowicz, Katarzyna
AU  - Vojnović, Sandra
AU  - Nikodinović-Runić, Jasmina
AU  - Savić, Vladimir
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4985
AB  - In the continuation of our study of substituted isocoumarins a series of novel 3-azolyl isocoumarin and their thio derivatives, including some related lactone compounds was prepared and biologically profiled against C. albicans showing moderate activity with MIC values in range of 4-60 μg mL-1, in general. The additional characterisation of selected compounds was carried out by exploring their activity on CYP3A4 and CYP2D6 enzymes, while experiments on mutagenicity were performed by AMES test. The representative isocoumarins 3b, 4a and 4b showed lower inhibitory activity on CYP enzymes, when compared to the reference inhibitors, ketoconazole and quinidine. Compound 4a showed a higher mutagenic potential than the other two compounds. Further characterization included cytotoxicity profiling against normal MRC5 cells.
AB  - Синтетисана је серија нових 3-азолил-изокумарина и сличних лактонских деривата и евалуирана је њихова антифунгална активност на Candida albicans, где су показали умерену активност (MIC 4–60 μg mL -1 ). Испитана је и интеракција одабраних изокума- ринских деривата са хуманим CYP3A4 и CYP2D6 ензимима помоћу луминисцентног теста, док им је мутагени потенцијал одређен AMES тестом. Испитивани изокумарини 3b, 4a и 4b не показују значајну интеракцију са наведеним CYP ензимима у поређењу сареферентним инхибиторима. Једињењe 4a показује већи мутагени потенцијал у односу на друга два. Додатна биолошка карактеризација је укључила одређивање цитотоксич- ности према нормалним MRC5 ћелијама.
PB  - Serbian Chemical Society
T2  - Journal of the Serbian Chemical Society
T1  - Synthesis and biological profiling of novel isocoumarin derivatives
and related compounds
T1  - СИНТЕЗА И БИОЛОШКО ПРОФИЛИСАЊЕ НОВИХ ИЗОКУМАРИНСКИХ ДЕРИВАТА И СЛИЧНИХ ЈЕДИЊЕЊА
VL  - 86
IS  - 7-8
SP  - 639
EP  - 649
DO  - 10.2298/JSC201201025S
ER  - 

@article{
author = "Simić, Milena and Erić, Slavica and Borić, Ivan and Lubelska, Annamaria and Latacz, Gneiwomir and Kiec-Kononowicz, Katarzyna and Vojnović, Sandra and Nikodinović-Runić, Jasmina and Savić, Vladimir",
year = "2021",
abstract = "In the continuation of our study of substituted isocoumarins a series of novel 3-azolyl isocoumarin and their thio derivatives, including some related lactone compounds was prepared and biologically profiled against C. albicans showing moderate activity with MIC values in range of 4-60 μg mL-1, in general. The additional characterisation of selected compounds was carried out by exploring their activity on CYP3A4 and CYP2D6 enzymes, while experiments on mutagenicity were performed by AMES test. The representative isocoumarins 3b, 4a and 4b showed lower inhibitory activity on CYP enzymes, when compared to the reference inhibitors, ketoconazole and quinidine. Compound 4a showed a higher mutagenic potential than the other two compounds. Further characterization included cytotoxicity profiling against normal MRC5 cells., Синтетисана је серија нових 3-азолил-изокумарина и сличних лактонских деривата и евалуирана је њихова антифунгална активност на Candida albicans, где су показали умерену активност (MIC 4–60 μg mL -1 ). Испитана је и интеракција одабраних изокума- ринских деривата са хуманим CYP3A4 и CYP2D6 ензимима помоћу луминисцентног теста, док им је мутагени потенцијал одређен AMES тестом. Испитивани изокумарини 3b, 4a и 4b не показују значајну интеракцију са наведеним CYP ензимима у поређењу сареферентним инхибиторима. Једињењe 4a показује већи мутагени потенцијал у односу на друга два. Додатна биолошка карактеризација је укључила одређивање цитотоксич- ности према нормалним MRC5 ћелијама.",
publisher = "Serbian Chemical Society",
journal = "Journal of the Serbian Chemical Society",
title = "Synthesis and biological profiling of novel isocoumarin derivatives
and related compounds, СИНТЕЗА И БИОЛОШКО ПРОФИЛИСАЊЕ НОВИХ ИЗОКУМАРИНСКИХ ДЕРИВАТА И СЛИЧНИХ ЈЕДИЊЕЊА",
volume = "86",
number = "7-8",
pages = "639-649",
doi = "10.2298/JSC201201025S"
}

Simić, M., Erić, S., Borić, I., Lubelska, A., Latacz, G., Kiec-Kononowicz, K., Vojnović, S., Nikodinović-Runić, J.,& Savić, V.. (2021). Synthesis and biological profiling of novel isocoumarin derivatives
and related compounds. in Journal of the Serbian Chemical Society
Serbian Chemical Society., 86(7-8), 639-649.
https://doi.org/10.2298/JSC201201025S

Simić M, Erić S, Borić I, Lubelska A, Latacz G, Kiec-Kononowicz K, Vojnović S, Nikodinović-Runić J, Savić V. Synthesis and biological profiling of novel isocoumarin derivatives
and related compounds. in Journal of the Serbian Chemical Society. 2021;86(7-8):639-649.
doi:10.2298/JSC201201025S .

Simić, Milena, Erić, Slavica, Borić, Ivan, Lubelska, Annamaria, Latacz, Gneiwomir, Kiec-Kononowicz, Katarzyna, Vojnović, Sandra, Nikodinović-Runić, Jasmina, Savić, Vladimir, "Synthesis and biological profiling of novel isocoumarin derivatives
and related compounds" in Journal of the Serbian Chemical Society, 86, no. 7-8 (2021):639-649,
https://doi.org/10.2298/JSC201201025S . .