title: Structure-retention behaviour of biologically active fused 1,2,4-triazinones--correlation with in silico molecular properties.
abstract: The chromatographic behaviour and significant lipophilicity/hydrophobicity indices (log k(w), S, φ(0)) are presented for 21 biologically active fused 1,2,4-triazinones based on the linear relationship: log k = log k(w)-Sφ established for the retention on LC-18 HPLC column, using as mobile phases mixtures of three organic modifiers with water. The effect of these mobile phase modifiers on the chromatographic behaviour of solutes was established and the organic modifier of choice is suggested. The complex correlation of slopes versus intercepts obtained for acetonitrile, contrary to linear ones obtained for methanol and dioxane are disclosed. The observed difference in retention mechanism for acetonitrile compared to methanol and dioxane is explained by intermolecular interactions encoded in lipophilicity. Linear correlations with statistically significant levels between log kw values determined from three different chromatographic systems were obtained. The relationships between log k(w) constants (derived from the linear model for methanol-water mobile phases) and predicted log P and log S values by the use of various computational methods were investigated and these were established with high correlation coefficients. The predicted log P values plotted against φ(0 (MeOH)) indices showed the best fit. Principal component analysis was used to compare various lipophilicity parameters of the solutes and their in silico biological descriptors relevant to optimal pharmacokinetics profile. The similarities and dissimilarities between all the variables and molecular structures of solutes are presented. Statistically significant correlations were found between the chromatographic lipophilicity indices and the calculated pharmacokinetic descriptors: fraction unbound in brain (f(u, brain)), oral bioavailability (%F), permeability and intestinal absorption in jejunum (Caco-2), skin permeation (log K(p)) and blood/brain concentration (log BB).
authors.affiliation: Chair and Department of Medical Chemistry, Medical University of Lublin, 4A Chodźki Street, 20-093 Lublin, Poland. Electronic address: malgorzata.sztanke@umlub.pl.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Sztanke
authors.affiliation: Department of Physical Chemistry, Chair of Chemistry, Faculty of Pharmacy with Medical Analytics Division, Medical University of Lublin, 4A Chodźki Street, 20-093 Lublin, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Tuzimski
authors.affiliation: Maria Curie-Skłodowska University, Faculty of Chemistry, Department of Physical Chemistry, Maria Curie-Skłodowska Sq. 3, 20-031 Lublin, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Janicka
authors.affiliation: Laboratory of Bioorganic Synthesis and Analysis, Chair and Department of Medical Chemistry, Medical University of Lublin, 4A Chodźki Street, 20-093 Lublin, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Sztanke
mesh_terms: D020003:1-Octanol / Q000737:chemistry; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D003198:Computer Simulation; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007408:Intestinal Absorption; D000432:Methanol / Q000737:chemistry; D008954:Models, Biological; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D012869:Skin Absorption; D012995:Solubility; D014227:Triazines / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D014867:Water / Q000737:chemistry
chemical_list: D014227:Triazines; D014867:Water; D020003:1-Octanol; D000432:Methanol
keywords: Bioactivity descriptors; Correlations; Hydrophobic parameters; PCA-based approach; RP-HPLC behaviour