Hansch equation hydrophobicity parameters

Fife and Xin (35) found that, under PTC conditions, the reaction between benzoyl chloride and a mixture of 1.0 equivalent of sodium p-toluate and 1.0 equivalent of sodium isobutyrate in the presence of 0,1 equivalent of pyridine 1-oxide gave an anhydride product mixture that contained approximately twice as much benzoic p-toluic anhydride as benzoic isobutyric anhydride on a molar basis (equation 7). Therefore, the process must include an important component that selects for the more lipophilic p-toluate ion. The differential partitioning of the competing carboxylate ions at the di-chloromethane-water interface is a reasonable explanation for this observed selectivity, because product composition correlates with the Hansch (39) hydrophobicity parameters for competing carboxylate ions (40). 

Five new pyridazinones were synthesized with substitutions in the two-position of the phenyl ring as given in Table II. Using the Hansch approach, correlations were made between the experimentally determined 18 2/18 3 ratios and the values and a,a values taken out of the data collection of Hansch and Leo (15) (Table II and Equations 1-3). The hydrophobic parameter is derived from the 1-octanol/water partition coefficient and o is the Hammett electronic parameter. 

As the equations show, linear correlations with the variables tr and a gave satisfactory results. This is certainly a simplification resulting from limited variance in the substituents. One would assume that square terms of the hydrophobic parameter are necessary in every correlation with biological activity not only to account for the random walk penetration process as in the original derivation of his equation by Hansch, but also, or even predominantly, as a description of the fact that numerous indifferent hydrophobic sites within the biological system compete with the site of action for the active molecule. In a first attempt we calculated regression equations for our hydrazones with the molecular parameter... 

Examining 18 substituted 3-phenylthio-1,1,1-trlfluoro-2-propanones, regression equations were obtained between the inhibitory activities and the Hammett (ct), Taft (E ) steric and Hansch (ir) hydrophobicity constants (H). In the fiope of increasing the significance of these equations and to better distinguish between the Importance of various substituent positions, several new compounds of the related structure were synthesized, a much larger set of substituent parameters was applied, and instead of the arbitrary choice of these values, the variables were selected into the equations by a more sophisticated tool, linear stepwise regression analysis. 

In a parallel development, structural effects on the chemical reactivity and physical properties of organic compounds were modelled quantitatively by the Hammett equation 8). The topic is well reviewed by Shorter 9>. Hansen 10) attempted to apply the Hammett equation to biological activities, while Zahradnik U) suggested an analogous equation applicable to biological activities. The major step forward is due to the work of Hansch and Fujita12), who showed that a correlation equation which accounted for both electrical and hydrophobic effects could successfully model bioactivities. In later work, steric parameters were included 13). 

Quantitative structure-activity relationship (QSAR) (Hansch and Klein, 1986 Hansch and Leo, 1995) represents an attempt to correlate structural descriptors of compounds with activities. The physicochemical descriptors include numerical parameters to account for electronic properties, steric effect, topology, and hydrophobicity of analogous compounds. In its simplest form, the biochemical activities are correlated to the numerical substituent descriptors of analogous compounds tested by a linear equation such as... 

The activity of 1,1jl-trifluoro 3-mercapto substituted phenyl propan-2-ones was not simply correlated with MR alone, therefore, a combination of Hammett a constant, Taft steric parameter (Eg) and Hansch hydrophobic constant (x) was included in the regression analysis. "Equation 36" was found to be of the best fit for compounds substituted in the meta and para positions. 

Roy and Leonard [183] have also presented QSAR models for the HIV-1 RT inhibitory activity of the thiazolidinones listed in Tables 16 and 17 along with some more similar analogues (Table 18) [184-187] using the hydrophobic-ity and molar refractivity, quantum chemical and topological and indicator parameters as descriptors. In this, the 3-pyridyls/phenyls (Tables 16 and 17) and 3-(pyrimidin-2-yls) (Table 18) [186] have become part of the dataset. Additionally, four compounds with the thiazolidin-4-thione nucleus have been included in the dataset. In Fujita-Ban [188] and mixed (Hansch and Fujita-Ban) approaches 7 to 17 descriptor models have been discovered for the cytopathicity effect (EC50) and cytotoxic effect (CC50) of the compounds. The following equations show the minimum descriptor models for each activity from this study. 

Hansch and Noser performed a QSAR work on the same group of haptenesj but separately for pyridine-substitution derivatives (N=22 r=0.92j k=4) and for benzene substitution derivatives (N=20j r=0.95j k=5).They used molecular refraction, NR, hydrophobicity, a-Hammett constants separately for ortho, meta, and para substituents, as structural variables, but only as a total of k=4 or 5 (k is here the number of structural parameters used in the regressional equation). Their regres-... 

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