Chromatographic and computational screening of anisotropic lipophilicity and pharmacokinetics of newly synthesized 1-aryl-3-ethyl-3-methylsuccinimides
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2020
Authors
Kovaević, StrahinjaKaradzić-Banjac, Milica
Podunavac-Kuzmanović, Sanja
Milošević, Nataša
Curcić, Jelena
Vulić, Jelena
Seregelj, Vanja
Banjac, Nebojša
Ušćumlić, Gordana
Article (Published version)
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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) indicat...e 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.
Keywords:
ADMET / Chromatography / Lipophilicity / Pharmacokinetics / QSRR / SuccinimideSource:
Computational Biology and Chemistry, 2020, 84Publisher:
- Elsevier Sci Ltd, Oxford
Funding / projects:
- Sustainable and green chemistry approach for environmental friendly analytical methods and energy storage (RS-MESTD-Basic Research (BR or ON)-172012)
- Study of the Synthesis, Structure and Activity of Natural and Synthetic Organic Compounds (RS-MESTD-Basic Research (BR or ON)-172013)
- Design, synthesis, characterization and assessment of practical applications of coordination and organometallic compounds (RS-MESTD-Basic Research (BR or ON)-172014)
DOI: 10.1016/j.compbiolchem.2019.107161
ISSN: 1476-9271
PubMed: 31787580
WoS: 000510947400019
Scopus: 2-s2.0-85076526384
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Institution/Community
Poljoprivredni fakultetTY - JOUR AU - Kovaević, 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://aspace.agrif.bg.ac.rs/handle/123456789/5331 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 = "Kovaević, 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" }
Kovaević, 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
Kovaević 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 .
Kovaević, 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 . .