TY  - JOUR
AU  - Kovačević, Strahinja
AU  - Karadzić-Banjac, Milica
AU  - Podunavac-Kuzmanović, Sanja
AU  - Milošević, Nataša
AU  - Curcić, Jelena
AU  - Vulić, Jelena
AU  - Seregelj, Vanja
AU  - Banjac, Nebojša
AU  - Ušćumlić, Gordana
PY  - 2020
UR  - http://TechnoRep.tmf.bg.ac.rs/handle/123456789/5885
AB  - The present study is focused on a series of newly synthesized 1-aryl-3-ethyl-3-methylsuccinimide derivatives, as potential anticonvulsants. The retention behavior of eleven succinimide derivatives was determined by using reversed phase high performance liquid chromatography (RP-HPLC) and reversed phase high performance thin layer chromatography (RP-HPTLC). The estimated retention behavior was correlated with partition (logP) and distribution coefficients (logD). These high correlations pointed out that the determined retention parameters (logK(0) and R-M(0)) can be considered chromatographic (anisotropic) lipophilicity of the studied succinimide derivatives. The structural properties, which dominantly affect the chromatographic lipophilicity, were determined as well. The significant correlations between the chromatographic lipophilicity and plasma protein binding (PPB), Madin-Darby Canine Kidney (MDCK) cells permeability, volume of distribution (Vd) and absorption constant (Ka) indicate the strong influence of lipophilicity on pharmacokinetics of 1-aryl-3-ethyl-3-methylsuccinimide derivatives. These derivatives have also been tested applying Comprehensive Medicinal Chemistry (CMC) drug-like rules which confirmed their drug-like properties. Besides, their blood-brain penetration (BBB) ability has been estimated applying the set of Clark's rules and by using Pre-ADMET software. Regarding toxicity, it was predicted that only one compound from the set might have toxic effects by blocking the hERG potassium channel. The present study reveals which molecular features in the structure of novel succinimide derivatives could be crucial for their lipophilicity, and consequently for their pharmacokinetic properties. The results indicate that the newly synthesized series of succinimide derivatives should be further considered in design of novel anticonvulsants.
PB  - Elsevier Sci Ltd, Oxford
T2  - Computational Biology and Chemistry
T1  - Chromatographic and computational screening of anisotropic lipophilicity and pharmacokinetics of newly synthesized 1-aryl-3-ethyl-3-methylsuccinimides
VL  - 84
DO  - 10.1016/j.compbiolchem.2019.107161
ER  - 

@article{
author = "Kovačević, Strahinja and Karadzić-Banjac, Milica and Podunavac-Kuzmanović, Sanja and Milošević, Nataša and Curcić, Jelena and Vulić, Jelena and Seregelj, Vanja and Banjac, Nebojša and Ušćumlić, Gordana",
year = "2020",
abstract = "The present study is focused on a series of newly synthesized 1-aryl-3-ethyl-3-methylsuccinimide derivatives, as potential anticonvulsants. The retention behavior of eleven succinimide derivatives was determined by using reversed phase high performance liquid chromatography (RP-HPLC) and reversed phase high performance thin layer chromatography (RP-HPTLC). The estimated retention behavior was correlated with partition (logP) and distribution coefficients (logD). These high correlations pointed out that the determined retention parameters (logK(0) and R-M(0)) can be considered chromatographic (anisotropic) lipophilicity of the studied succinimide derivatives. The structural properties, which dominantly affect the chromatographic lipophilicity, were determined as well. The significant correlations between the chromatographic lipophilicity and plasma protein binding (PPB), Madin-Darby Canine Kidney (MDCK) cells permeability, volume of distribution (Vd) and absorption constant (Ka) indicate the strong influence of lipophilicity on pharmacokinetics of 1-aryl-3-ethyl-3-methylsuccinimide derivatives. These derivatives have also been tested applying Comprehensive Medicinal Chemistry (CMC) drug-like rules which confirmed their drug-like properties. Besides, their blood-brain penetration (BBB) ability has been estimated applying the set of Clark's rules and by using Pre-ADMET software. Regarding toxicity, it was predicted that only one compound from the set might have toxic effects by blocking the hERG potassium channel. The present study reveals which molecular features in the structure of novel succinimide derivatives could be crucial for their lipophilicity, and consequently for their pharmacokinetic properties. The results indicate that the newly synthesized series of succinimide derivatives should be further considered in design of novel anticonvulsants.",
publisher = "Elsevier Sci Ltd, Oxford",
journal = "Computational Biology and Chemistry",
title = "Chromatographic and computational screening of anisotropic lipophilicity and pharmacokinetics of newly synthesized 1-aryl-3-ethyl-3-methylsuccinimides",
volume = "84",
doi = "10.1016/j.compbiolchem.2019.107161"
}

Kovačević, S., Karadzić-Banjac, M., Podunavac-Kuzmanović, S., Milošević, N., Curcić, J., Vulić, J., Seregelj, V., Banjac, N.,& Ušćumlić, G.. (2020). Chromatographic and computational screening of anisotropic lipophilicity and pharmacokinetics of newly synthesized 1-aryl-3-ethyl-3-methylsuccinimides. in Computational Biology and Chemistry
Elsevier Sci Ltd, Oxford., 84.
https://doi.org/10.1016/j.compbiolchem.2019.107161

Kovačević S, Karadzić-Banjac M, Podunavac-Kuzmanović S, Milošević N, Curcić J, Vulić J, Seregelj V, Banjac N, Ušćumlić G. Chromatographic and computational screening of anisotropic lipophilicity and pharmacokinetics of newly synthesized 1-aryl-3-ethyl-3-methylsuccinimides. in Computational Biology and Chemistry. 2020;84.
doi:10.1016/j.compbiolchem.2019.107161 .

Kovačević, Strahinja, Karadzić-Banjac, Milica, Podunavac-Kuzmanović, Sanja, Milošević, Nataša, Curcić, Jelena, Vulić, Jelena, Seregelj, Vanja, Banjac, Nebojša, Ušćumlić, Gordana, "Chromatographic and computational screening of anisotropic lipophilicity and pharmacokinetics of newly synthesized 1-aryl-3-ethyl-3-methylsuccinimides" in Computational Biology and Chemistry, 84 (2020),
https://doi.org/10.1016/j.compbiolchem.2019.107161 . .

TY  - JOUR
AU  - Milošević, Nataša P.
AU  - Kojić, Vesna
AU  - Curcić, Jelena
AU  - Jakimov, Dimitar
AU  - Milić, Nataša
AU  - Banjac, Nebojša
AU  - Ušćumlić, Gordana
AU  - Kaliszan, Roman
PY  - 2017
UR  - http://TechnoRep.tmf.bg.ac.rs/handle/123456789/5819
AB  - Design of a new drug entity is usually preceded by analysis of quantitative structure activity (properties) relationships, QSA(P)R. Six newly synthesized succinimide derivatives have been determined for (i) in silico physico-chemical descriptors, pharmacokinetic and toxicity predictors, (ii) in vitro biological activity on four different carcinoma cell lines and on normal fetal lung cells and (iii) lipophilicity on liquid chromatography. All compounds observed were predicted for good permeability and solubility, good oral absorption rate and moderate volume of distribution as well as for modest blood brain permeation, followed by acceptable observed toxicity. In silico determined lipophilicity, permeability through jejunum and aqueous solubility were correlated with experimentally obtained lipophilic constants (by use of high pressure liquid chromatography) and linear correlations were obtained. Absorption rate and volume of distribution were predicted by chromatographic lipophilicity measurements while permeation through blood bran barrier was predicted dominantly by molecular size defined with molecular weight. Five compounds have demonstrated antiproliferative activity toward cervix carcinoma HeLa cell lines; three were cytotoxic against breast carcinoma MCF-7 cells, while one inhibited proliferation of colon carcinoma HT 29 cell lines. Only one compound was cytotoxic toward normal cell lines, while other compounds were proven as safe. Antiproliferative potential against HeLa cells was described as exponential function of lipophilicity. Based on obtained results, lead compounds were selected.
PB  - Elsevier Science Bv, Amsterdam
T2  - Journal of Pharmaceutical and Biomedical Analysis
T1  - Evaluation of in silico pharmacokinetic properties and in vitro cytotoxic activity of selected newly synthesized N-succinimide derivatives
EP  - 257
SP  - 252
VL  - 137
DO  - 10.1016/j.jpba.2017.01.042
ER  - 

@article{
author = "Milošević, Nataša P. and Kojić, Vesna and Curcić, Jelena and Jakimov, Dimitar and Milić, Nataša and Banjac, Nebojša and Ušćumlić, Gordana and Kaliszan, Roman",
year = "2017",
abstract = "Design of a new drug entity is usually preceded by analysis of quantitative structure activity (properties) relationships, QSA(P)R. Six newly synthesized succinimide derivatives have been determined for (i) in silico physico-chemical descriptors, pharmacokinetic and toxicity predictors, (ii) in vitro biological activity on four different carcinoma cell lines and on normal fetal lung cells and (iii) lipophilicity on liquid chromatography. All compounds observed were predicted for good permeability and solubility, good oral absorption rate and moderate volume of distribution as well as for modest blood brain permeation, followed by acceptable observed toxicity. In silico determined lipophilicity, permeability through jejunum and aqueous solubility were correlated with experimentally obtained lipophilic constants (by use of high pressure liquid chromatography) and linear correlations were obtained. Absorption rate and volume of distribution were predicted by chromatographic lipophilicity measurements while permeation through blood bran barrier was predicted dominantly by molecular size defined with molecular weight. Five compounds have demonstrated antiproliferative activity toward cervix carcinoma HeLa cell lines; three were cytotoxic against breast carcinoma MCF-7 cells, while one inhibited proliferation of colon carcinoma HT 29 cell lines. Only one compound was cytotoxic toward normal cell lines, while other compounds were proven as safe. Antiproliferative potential against HeLa cells was described as exponential function of lipophilicity. Based on obtained results, lead compounds were selected.",
publisher = "Elsevier Science Bv, Amsterdam",
journal = "Journal of Pharmaceutical and Biomedical Analysis",
title = "Evaluation of in silico pharmacokinetic properties and in vitro cytotoxic activity of selected newly synthesized N-succinimide derivatives",
pages = "257-252",
volume = "137",
doi = "10.1016/j.jpba.2017.01.042"
}

Milošević, N. P., Kojić, V., Curcić, J., Jakimov, D., Milić, N., Banjac, N., Ušćumlić, G.,& Kaliszan, R.. (2017). Evaluation of in silico pharmacokinetic properties and in vitro cytotoxic activity of selected newly synthesized N-succinimide derivatives. in Journal of Pharmaceutical and Biomedical Analysis
Elsevier Science Bv, Amsterdam., 137, 252-257.
https://doi.org/10.1016/j.jpba.2017.01.042

Milošević NP, Kojić V, Curcić J, Jakimov D, Milić N, Banjac N, Ušćumlić G, Kaliszan R. Evaluation of in silico pharmacokinetic properties and in vitro cytotoxic activity of selected newly synthesized N-succinimide derivatives. in Journal of Pharmaceutical and Biomedical Analysis. 2017;137:252-257.
doi:10.1016/j.jpba.2017.01.042 .

Milošević, Nataša P., Kojić, Vesna, Curcić, Jelena, Jakimov, Dimitar, Milić, Nataša, Banjac, Nebojša, Ušćumlić, Gordana, Kaliszan, Roman, "Evaluation of in silico pharmacokinetic properties and in vitro cytotoxic activity of selected newly synthesized N-succinimide derivatives" in Journal of Pharmaceutical and Biomedical Analysis, 137 (2017):252-257,
https://doi.org/10.1016/j.jpba.2017.01.042 . .