Quantitative structure–activity relationship to predict acute fish toxicity of organic solvents
A. LevetClaire BordesYohann ClémentPierre MignonHenry ChermettePedro MaroteCécile Cren‐OlivéPierre Lantéri
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Keywords:
Aquatic toxicology
Molecular descriptor
Lipophilicity
Octanol
Lipophilicity
Octanol
Micellar solutions
Aqueous two-phase system
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The linear solvation equation approach has been used to describe the octanol/water lipophilicity scale (logPoct) and the isocratic retention factors (log k) obtained using reversed phase HPLC with acetonitrile. Both the octanol/water partition coefficients and the RP-HPLC retention data obtained from the literature, showed good correlation with the molecular descriptors such as size, excess molar refractivity, H-bond acidity/basicity, and polarity/dipolarity. However, the impact of the H-bond acidity term was very different on the two lipophilicity scales. The H-bond acidity term was not significant in describing the octanol/water lipophilicity, while the H-bond acidity of the molecules decreased significantly their RP-HPLC retention. As the other terms had very similar impact on the two lipophilicity scales, it made it possible to convert one scale to the other by incorporating only the H-bond acidity of the compounds as is shown by the equation below, where A is the compound H-bond acidity. Using the simpler hydrogen bond donor counts (HBC) also helped to align the two lipophilicity scales to each other. The validity of the above equations was tested using a test set of 41 drug compounds with our measured data. The log Poct values were estimated from isocratic RP-HPLC retention data with the H-bond acidity term and counts, with an error of 0.284 and 0.325 log unit, respectively.
Lipophilicity
Octanol
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The retention behavior of newly synthesized compounds with antimycotic activity from the 2-(2,4-dihydroxyphenyl)benzothiazole group by high-performance liquid chromatography has been investigated. RP-18 stationary phase and methanol-acetate buffer aqueous mobile phases at pH 4 and 7.4 have been used. In the case of the mobile phase at pH 7.4, higher concentrations of water can be applied than at pH 4. The studied compounds showed regular retention behavior, their log k values decreasing linearly with an increasing concentration of methanol in the mobile phase. On the basis of these relationships, the lipophilicity (log kw), specific hydrophobic surface area (S), and isocratic chromatographic hydrophobicity index (psi0) were determined. Similar log kw values and sensitivity to changes in the structure of compounds studied for both mobile phases have been found. Moderate correlations between the chromatographic parameters and the calculated octanol-water log P values were found. Finally, the lipophilicity parameters were compared with the fungistatic properties of compounds expressed by log MIC (minimum inhibitory concentration) values to find quantitative structure activity relationship equations.
Lipophilicity
Octanol
Benzothiazole
Kovats retention index
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Apparent partition coefficients in n-octanol-buffer system, solubility in the buffers, and retention by mitochondria from rat liver, by Mycobacterium phlei and by Saccharomyces cerevisiae (after 10 min incubation) have been characterized for 13 arylsubstituted phenylhydrazonopropanedinitrile derivatives. Regression analysis has shown linear dependence of logarithms of the apparent partition coefficients on the published π parameters characterizing lipophilicity of the substituents. The apparent partition coefficients are inversely proportional to the solubility of the phenylhydrazonopropanedinitriles. The retention by the biosystems studied increases linearly with increasing lipophilicity, being independent of reactivity of the phenylhydrazonopropanedinitriles. The non-linear dependence of concentration of the phenylhydrazonopropanedinitriles remaining in the medium on the lipophilicity indicates that a lipophilic-hydrophilic equilibrium is established in the given time. The retained amount of the derivatives tested decreases with increasing pH values. The dependences are Z-shaped and have been described by the equations derived from the model presented by application of non-linear regression analysis.
Lipophilicity
Octanol
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Lipophilicity of chemicals and drug candidates is normally described in terms of octanol/water partitioning and log P. We investigated an alternate approach to lipophilicity determination using a mimic of an alkyl alcohol with compound partitioning quantified using acoustic sensing. A self-assembled monolayer composed of HSC10(CH2CH2O)6C18 was formed on planar gold electrodes of a piezoelectric acoustic sensor. The system was challenged with compounds covering a 4-log range of log D values. As compounds partitioned in the interfacial layer, changes in sensor resonant frequency were found to correlate with compound partition coefficients (log P) and with distribution coefficients (log D). Linear concordance (R2 = 0.933) was established between log(−dF/Mwt) and log P and with log D in both water and biological buffers at variant pH (pH 5.2 to 7.8). In turn, drug pKa could be determined by profiling log D changes during pH titration. The lipophilicity/pH profile of a weakly basic drug (quinine; pKa = 7.95) was sigmoidal with respect to −dF/Mw values, with a profile inverse to that of a weakly acidic drug (naproxen; pKa = 4.15).
Lipophilicity
Octanol
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The lipophilicity of cholesterol was investigated by using coarse-grained molecular dynamics and umbrella sampling. The previous coarse-grained cholesterol models in the literature are more hydrophobic than our model. The Gibbs free energy of transferring cholesterol from the octanol phase to water phase (ΔGo/w) was 11.88 ± 0.08 kcal mol–1, and the octanol–water partitioning coefficient (logP) was estimated to be 8.72 ± 0.06. The latter is in agreement with the logP values found by bioinformatics, which are standard methods to predict the lipophilicity, giving excellent octanol/water partitioning coefficients compared with experimental ones for different molecules. We also performed the first experimentally direct measurement of this important property for cholesterol. The experimental octanol/water partitioning coefficient of cholesterol was measured to be 8.86 ± 0.79, which is in excellent agreement with our calculated logP value from our parametrized coarse-grained cholesterol model. This shows the significance of systematic optimization of the lipophilicity for developing coarse-grain models of important biomolecules with complicated molecular structures and hydrophobic character like cholesterol.
Lipophilicity
Octanol
Biomolecule
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Lipophilicity
Octanol
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Lipophilicity
Octanol
Hexadecane
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The work covers synthesis and lipophilicity estimation of several BODIPY dyes. For these compounds, the distribution between 1-octanol and water layers is experimentally described and the corresponding partition coefficients LogP are calculated. The experimental LogP values are compared with popular fragment-based methods XLopP3, ALogPS, WLogP, SILICOS-IT and MLogP. Additionally, the hydrophobic and polar surface areas are found with quantum-mechanical calculations. That allowed to find a correlation between the LogP coefficient and the molecular surface topology, as well as to determine the corresponding incremental values of the methyl, acetyl, and phenyl substituents.
Lipophilicity
Octanol
BODIPY
Polar surface area
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