Hydrophobicity constant

The hydrophobic constant r is a measure of the contribution of a substituent X to the lipophilidty of compound R-X compared with R-H. The constant representing the solvent/solvent system, analogously to Hammett s p constant for the reaction type, was arbitrarily set to 1 for octanol/water and thus does not appear in Eq. (7). The lipophilidty constant ti allows the estimation of log P values for congeneric series of compounds with various substituents (see Eq. (8)). 

In subsequent studies attempting to find a correlation of physicochemical properties and antimicrobial activity, other parameters have been employed, such as Hammett O values, electronic distribution calculated by molecular orbital methods, spectral characteristics, and hydrophobicity constants. No new insight on the role of physiochemical properties of the sulfonamides has resulted. Acid dissociation appears to play a predominant role, since it affects aqueous solubiUty, partition coefficient and transport across membranes, protein binding, tubular secretion, and reabsorption in the kidneys. An exhaustive discussion of these studies has been provided (10). 

M. A., Brent, D. A. A comprehensive method for determining hydrophobicity constants by reversed-phase high-performance liquid chromatography. 

One approach is to extend the columns of a measurement table by means of their powers and cross-products. An example of such non-linear PCA is discussed in Section 37.2.1 in an application of QSAR, where biological activity was known to be related to the hydrophobic constant by means of a quadratic function. In this case it made sense to add the square of a particular column to the original measurement table. This procedure, however, tends to increase the redundancy in the data. 

Minick, D. J., Frenz, J. H., Patrick, M. A. 8c Brent, D. A. A comprehensive method for determining hydrophobicity constants by reversed-phase high-performance liquid chromatography. /. Med. Chem. 31, 1923-1933 (1988). 

Pleiss, M.A. and Grunewald, G.L. An extension of the f-fragment method for the calculation of hydrophobic constants (Log F) of conformationally defined systems, / Merf Chem., 26(12) 1760-1764,1983. 

A convenient way of estimating the lipophilicity of a ligand consists in using the lipophilicity increments n determined by Hansch for various structural fragments and groups of atoms (39—41). The hydrophobic constant nx for a substituent X is given by the following relation ... 

Table 5. Values of the hydrophobic constant nx for various groups X (41)...

The substituent hydrophobicity constant, based on partition coefficients analogs to Hammet constants ... 

Regression analysis is currently the most widely used correlative method in drug design. This is because it simplifies problems within a set of compounds by using a limited number of descriptors, notably the Hansch hydrophobic constant n, Hammet constants, or other electronic characteristics of substituents, and the Taft steric constant Eg. 

From determinations of the partitioning of several series of substituted compounds between n-octanol and water, C. Hansch and coworkers found that many substituents make a constant, and additive, contribution to the hydrophobicity of the parent compound. If the ratio of the solubility of the parent compound (H—S) in the organic phase to that in the aqueous phase is P0, and that of the substituted compound (R—S) is P, then the hydrophobicity constant for the substituent R, 7r, is defined by... 

Rekker, R.F. (1977) The Hydrophobic Constants Its Derivation and Application A Means of Characterizing Membrane Systems. Elsevier Scientific Publishing Company, New York. 

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. 

The 95% confidence intervals of the coefficients in Equations 11 and 12 indicated little significance of the electronic and steric parameters of the ortho substituents. In fact, better correlations were obtained when they were omitted and further separation of the hydrophobic constants was introduced as in Equations 13 and 14. All the parameters are highly significant except the linear w term for the ortho substituents (tt ). The correlation coefficient and standard deviation improved only slightly when a ( 2-4)2 term was added, as shown in Equation 15 (Figure 6). 

One can obtain some estimate of the surface polarity of a protein of known structure and hence its retention on a reversed-phase column by a consideration of the polarity of the side-chain functional groups. Such calculations have been carried out by a number of authors for amino acids (2S, 37) and peptides (35,42). The best correlation between the retention of a peptide (up to 15 residues) and its structure is obtained by the sum of the absolute fragmental hydrophobic constants (41) of the five most strongly hydrophobic residues (Trp, Phe, Leu, He, and Tyr). 

Aroma compounds selected were isoamyl alcohol (lOOpL/L), isoamyl acetate (lOOpL/L), ethyl hexanoate (lOOpL/L), ethyl octanoate (40pL/L), ethyl decanoate (lOpL/L), octanal (lOOpL/L), P-ionone (lOOpL/L), y-decalactone (lOOpL/L), supplied by Aldrich (Steinheim, Germany). They are all slightly soluble in water except for isoamyl alcohol which is soluble in water. The hydrophobic constants of volatile compounds are expressed by Log P where P is the partition coefficient of the compound in water/octanol system. 

The hydrophobic nature of the volatile substance seemed an important factor. The volatile compound with the highest hydrophobic constant (log P = 3.88), ethyl octanoate, is bound to a larger extent on yeast walls. Conversely, isoamyl alcohol, with log P= 1.21, is less fixed the decrease in volatility is 9%. 

Aroma compound logP hydrophobicity constant Sodium caseinate... 

Px and Ph represent the partition coefficients of a derivative and the parent molecule, respectively. Fujita and Hansch then combined these hydrophobic constants with Hammett s electronic constants to yield the linear Hansch equation and its many extended forms (19). 

Substituent electronic constants used to derive simple QSRR for real retention prediction potency have seldom succeeded. A wider application in that respect found the Hansch substituent hydrophobic constants, n 8], and Dross et al. [64] or Hansch and Leo [65] fragmental hydrophobic constants, /. The sums of these constants (plus corrections due to intramolecular interactions) account for the retention in reversed-phase liquid chromatographic systems [7,12). 

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