Correlation between structure, retention, property, and activity of biologically relevant 1,7-bis(aminoalkyl)diazachrysene derivatives
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2013
Authors
Šegan, Sandra
Trifković, Jelena

Verbić, Tatjana

Opsenica, Dejan

Zlatović, Mario

Burnett, James
Šolaja, Bogdan

Milojković-Opsenica, Dušanka

Article (Published version)

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The physicochemical properties, retention parameters (R-M(0)), partition coefficients (log P-OW), and pK(a) values for a series of thirteen 1,7-bis(aminoalkyl) diazachrysene (1,7-DAAC) derivatives were determined in order to reveal the characteristics responsible for their biological behavior. The investigated compounds inhibit three unrelated pathogens (the Botulinum neurotoxin serotype A light chain (BoNT/A LC), Plasmodium falciparum malaria, and Ebola filovirus) via three different mechanisms of action. To determine the most influential factors governing the retention and activities of the investigated diazachrysenes, R-M(0), log P-OW, and biological activity values were correlated with 2D and 3D molecular descriptors, using a partial least squares regression. The resulting quantitative structure-retention (property) relationships indicate the importance of descriptors related to the hydrophobicity of the molecules (e.g., predicted partition coefficients and hydrophobic surface area...). Quantitative structure-activity relationship models for describing biological activity against the BoNT/A LC and malarial strains also include overall compound polarity, electron density distribution, and proton donor/acceptor potential. Furthermore, models for Ebola filovirus inhibition are presented qualitatively to provide insights into parameters that may contribute to the compounds' antiviral activities. Overall, the models form the basis for selecting structural features that significantly affect the compound's absorption, distribution, metabolism, excretion, and toxicity profiles.
Keywords:
1,7-Bis(aminoalkyl)-diazachrysene derivatives (1,7-DAAC) / Lipophilicity / Acidity constants / Quantitative structure-retention relationship (QSRR) / Quantitative structure-activity relationship (QSAR)Source:
Journal of Pharmaceutical and Biomedical Analysis, 2013, 72, 231-239Publisher:
- Elsevier
Funding / projects:
- The synthesis of aminoquinoline-based antimalarials and botulinum neurotoxin A inhibitors (RS-172008)
- National Cancer Institute, National Institutes of Health (USA) [HHSN261200800001E]
- NATOs Public Diplomacy Division [SfP983638]
DOI: 10.1016/j.jpba.2012.08.025
ISSN: 0731-7085
PubMed: 22985530
WoS: 000311819100033
Scopus: 2-s2.0-84869079937
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IHTMTY - JOUR AU - Šegan, Sandra AU - Trifković, Jelena AU - Verbić, Tatjana AU - Opsenica, Dejan AU - Zlatović, Mario AU - Burnett, James AU - Šolaja, Bogdan AU - Milojković-Opsenica, Dušanka PY - 2013 UR - https://cer.ihtm.bg.ac.rs/handle/123456789/1305 AB - The physicochemical properties, retention parameters (R-M(0)), partition coefficients (log P-OW), and pK(a) values for a series of thirteen 1,7-bis(aminoalkyl) diazachrysene (1,7-DAAC) derivatives were determined in order to reveal the characteristics responsible for their biological behavior. The investigated compounds inhibit three unrelated pathogens (the Botulinum neurotoxin serotype A light chain (BoNT/A LC), Plasmodium falciparum malaria, and Ebola filovirus) via three different mechanisms of action. To determine the most influential factors governing the retention and activities of the investigated diazachrysenes, R-M(0), log P-OW, and biological activity values were correlated with 2D and 3D molecular descriptors, using a partial least squares regression. The resulting quantitative structure-retention (property) relationships indicate the importance of descriptors related to the hydrophobicity of the molecules (e.g., predicted partition coefficients and hydrophobic surface area). Quantitative structure-activity relationship models for describing biological activity against the BoNT/A LC and malarial strains also include overall compound polarity, electron density distribution, and proton donor/acceptor potential. Furthermore, models for Ebola filovirus inhibition are presented qualitatively to provide insights into parameters that may contribute to the compounds' antiviral activities. Overall, the models form the basis for selecting structural features that significantly affect the compound's absorption, distribution, metabolism, excretion, and toxicity profiles. PB - Elsevier T2 - Journal of Pharmaceutical and Biomedical Analysis T1 - Correlation between structure, retention, property, and activity of biologically relevant 1,7-bis(aminoalkyl)diazachrysene derivatives VL - 72 SP - 231 EP - 239 DO - 10.1016/j.jpba.2012.08.025 ER -
@article{ author = "Šegan, Sandra and Trifković, Jelena and Verbić, Tatjana and Opsenica, Dejan and Zlatović, Mario and Burnett, James and Šolaja, Bogdan and Milojković-Opsenica, Dušanka", year = "2013", abstract = "The physicochemical properties, retention parameters (R-M(0)), partition coefficients (log P-OW), and pK(a) values for a series of thirteen 1,7-bis(aminoalkyl) diazachrysene (1,7-DAAC) derivatives were determined in order to reveal the characteristics responsible for their biological behavior. The investigated compounds inhibit three unrelated pathogens (the Botulinum neurotoxin serotype A light chain (BoNT/A LC), Plasmodium falciparum malaria, and Ebola filovirus) via three different mechanisms of action. To determine the most influential factors governing the retention and activities of the investigated diazachrysenes, R-M(0), log P-OW, and biological activity values were correlated with 2D and 3D molecular descriptors, using a partial least squares regression. The resulting quantitative structure-retention (property) relationships indicate the importance of descriptors related to the hydrophobicity of the molecules (e.g., predicted partition coefficients and hydrophobic surface area). Quantitative structure-activity relationship models for describing biological activity against the BoNT/A LC and malarial strains also include overall compound polarity, electron density distribution, and proton donor/acceptor potential. Furthermore, models for Ebola filovirus inhibition are presented qualitatively to provide insights into parameters that may contribute to the compounds' antiviral activities. Overall, the models form the basis for selecting structural features that significantly affect the compound's absorption, distribution, metabolism, excretion, and toxicity profiles.", publisher = "Elsevier", journal = "Journal of Pharmaceutical and Biomedical Analysis", title = "Correlation between structure, retention, property, and activity of biologically relevant 1,7-bis(aminoalkyl)diazachrysene derivatives", volume = "72", pages = "231-239", doi = "10.1016/j.jpba.2012.08.025" }
Šegan, S., Trifković, J., Verbić, T., Opsenica, D., Zlatović, M., Burnett, J., Šolaja, B.,& Milojković-Opsenica, D.. (2013). Correlation between structure, retention, property, and activity of biologically relevant 1,7-bis(aminoalkyl)diazachrysene derivatives. in Journal of Pharmaceutical and Biomedical Analysis Elsevier., 72, 231-239. https://doi.org/10.1016/j.jpba.2012.08.025
Šegan S, Trifković J, Verbić T, Opsenica D, Zlatović M, Burnett J, Šolaja B, Milojković-Opsenica D. Correlation between structure, retention, property, and activity of biologically relevant 1,7-bis(aminoalkyl)diazachrysene derivatives. in Journal of Pharmaceutical and Biomedical Analysis. 2013;72:231-239. doi:10.1016/j.jpba.2012.08.025 .
Šegan, Sandra, Trifković, Jelena, Verbić, Tatjana, Opsenica, Dejan, Zlatović, Mario, Burnett, James, Šolaja, Bogdan, Milojković-Opsenica, Dušanka, "Correlation between structure, retention, property, and activity of biologically relevant 1,7-bis(aminoalkyl)diazachrysene derivatives" in Journal of Pharmaceutical and Biomedical Analysis, 72 (2013):231-239, https://doi.org/10.1016/j.jpba.2012.08.025 . .