Substituent hydrophobicity constant

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

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). 

Fortunately, partition coefficients can be calculated by knowing the contribution that various substituents make to hydrophobicity. This contribution is known as the substituent hydrophobicity constant (it). 

The substituent hydrophobicity constant is a measure of how hydrophobic a substituent is, relative to hydrogen. The value can be obtained as follows. Partition coefficients are measured experimentally for a standard compound with and without a... 

QSAR equations relating biological activity to the partition coefficient P have already been described, but there is no reason why the substituent hydrophobicity constant tt cannot be used in place of P if only the substituents are being varied. 

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)). 

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 ... 

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... 

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). 

This parameter is often used as a substituent steric constant in - Hansch analysis. In order to put the molar refractivities of the substituents on approximately the same scale as the - hydrophobic substituent constants Jt, the substituent MR values are often scaled down by the factor 0.1. 

Well-known substituent descriptors are the substituent constants which are experimentally determined descriptors among them, - electronic substituent constants, steric substituent descriptors, and lipophilicity substituent descriptors such as - Hansch-Fujita hydrophobic constants are the most commonly used in QSAR/QSPR modelling. 

The analysis of the parameters representing the effect of the medium in terms of extrathermodynamical relations has shown (see above, section A.2) that the hydrophobic substituent constant it depends on the molecules from which it is derived. For example, hydrophobic constants derived from the octanol/water partition coefficients of aromatic molecules differ from those obtained from aliphatic molecules (112). Collander s equation (111) provides the empirical basis for the evaluation of logP values for the same molecule in different solvents. However, solvents with markedly different solvation properties (e.g., hydrogen bonding ability) do not conform to Collander s equation (see below, section C.3). 

From the Hammett equation [Hammett, 1935, 1937], the seminal vork of Hammett gave rise to the a—p culture in the delineation of substituent effects on organic reactions, whose aim was to search for linear free energy relationships (LFER) [Hammett, 1938] steric, electronic, and hydrophobic constants were derived for several substituents and used in an additive model to estimate the biological activity of congeneric series of compounds. 

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. 

Hydrophobic parameters are mostly experimentally obtained log P or calculated log P (C log P), where P is the octanol-water partition coefficient. n is the hydrophobic constant of the substituents. The electronic parameters (Hammett constants) a, a and appHes to substituent effects on aromatic systems and Taft s a appHes to ahphatic systems. Steric parameters are Tafts steric parameter Es, McGowan volume MgVol, van der Waals volume Vw, molecular weight MW. Verloop s sterimol parameters Bl, B5 and L... 

Sum of hydrophobicity constants for aryl substituents excluding the boronic acid. 

Thus, the Hansch-Fujita approach allows one to calculate the partition coefficient of any substituted compound knowing the partition coefficient of the parent compound (RH) and the hydrophobic constants of substituents X, (Eq. [11]) ... 

This is true in particular for the (erroneous) zero value of the hydrophobic constant of H (iTh = 0.00 by definition), the limited number of experimental log P values used to derive hydrophobic substituent constants, and the number of different tt scales needed to account for the complex electronic effects operating in polysubstituted aromatic compounds. Despite several attempts to extend the applicability of log P calculations using the Hansch-Fujita approach, for instance, by inclusion of correction factors" and better treatments of electronic effects , this approach has fallen into obso-lesence when it comes to calculating log P values. In contrast, the hydrophobic substituent constants (nx) of Table 1 continue to find use as structural parameters in some QSAR studies. ... 

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