title: Correlation between structure, retention, property, and activity of biologically relevant 1,7-bis(aminoalkyl)diazachrysene derivatives.
abstract: The physicochemical properties, retention parameters (R(M)(0)), partition coefficients (logP(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), logP(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.
authors.affiliation: Institute of Chemistry, Technology and Metallurgy, University of Belgrade, Njegoševa 12, 11000 Belgrade, Serbia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Šegan
authors.forename: Jelena
authors.initials: J
authors.lastname: Trifković
authors.forename: Tatjana
authors.initials: T
authors.lastname: Verbić
authors.forename: Dejan
authors.initials: D
authors.lastname: Opsenica
authors.forename: Mario
authors.initials: M
authors.lastname: Zlatović
authors.forename: James
authors.initials: J
authors.lastname: Burnett
authors.forename: Bogdan
authors.initials: B
authors.lastname: Šolaja
authors.forename: Dušanka
authors.initials: D
authors.lastname: Milojković-Opsenica
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology*; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors; D029043:Ebolavirus / Q000187:drug effects; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D008288:Malaria / Q000188:drug therapy; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects; D025341:Principal Component Analysis; D021281:Quantitative Structure-Activity Relationship; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000890:Anti-Infective Agents; D000962:Antimalarials; D000998:Antiviral Agents; D011804:Quinolines; D019274:Botulinum Toxins, Type A