Quantitative structure-activity relationship partition constants

There is a continuing effort to extend the long-established concept of quantitative-structure-activity-relationships (QSARs) to quantitative-structure-property relationships (QSPRs) to compute all relevant environmental physical-chemical properties (such as aqueous solubility, vapor pressure, octanol-water partition coefficient, Henry s law constant, bioconcentration factor (BCF), sorption coefficient and environmental reaction rate constants from molecular structure). 

Statistical and computational methods have been used to quantify structure-activi relationships leading to quantitative structure-activity relationships (QSAR). The concqpt of QSAR can be dated back to the work of Crum, Brown and Fraser from 1868 to 1869, and Richardson, also in 1869. Many notable papers were published in the period leading up to the twentieth century by men such as Berthelot and Jungfleisch in 1872, Nemst in 1891, Ov ton in 1897 and Meyer in 1899 (7). Professor Corwin Hansch is now regarded by many as the father of QSAR, because of his work in the development of new and innovative techniques for QSAR. He and his co-woikers produced a paper that was to be known as the birtii of QSAR, and was oititled "Correlation of biological activity of phenoxyacetic acids with Hammett substituent constants and partition coefficients" (2). 

MLC has been applied for the determination of partition properties and the hydropho-bicity of monosubstituted phenols. The enthalpy and entropy of partition were estimated from the temperature dependence of the partition properties these values were interpreted in terms of molecular size and the ability of the solute to establish a hydrogen bond. The 7T, jt(H) and jt(S) constants were determined from the experimental partition properties and applied to quantitative structure-activity relationship (QSAR) analysis . 

BR is the relative biologic activity under investigation, for example the molar EDr>o or the percent response at a given dose. Log P is the logarithm of the octanol-water partition coefficient, a is the approprite Hammett signa constant (electronic in nature), and Es is the Taft steric parameter. With the important demonstration by Hansch that the partition coefficient is often an additive constitutive property, all of the physical parameers may be obtained from the literature. A second important contribution by Hansch is the recognition that the use of statistical techniques is essential to the analysis of quantitative structure-activity relationships. To develop an equation such as that above, one feeds the... 

Furthermore, for some cationic surfactants, quantitative structure-activity relationships have been established for daphnids and fish. Increments used in the ECOSAR toxicity estimation software (Syracuse Research Center, freely available from the US Environmental Protection Agency as part of the software EPI Suite) are -0.13 and -0.37 for each carbon atom in monoalkyl quaternary ammonium surfactants in daphnids and fish, respectively. These increments are much smaller than the ones found here. Our increments for the n-alkyl chain in Rj position are more in accordance with increments for CH2 groups in n-octanol/water partitioning constant estimation procedures, which are, e.g., 0.66 and 0.49 in Hansch and Leo s method and Meylan and Howard s method, respectively [20]. This suggests that uptake into the cells is governed by lipophilicity, or maybe more exactly by membrane/water partitioning [21, 22]. 

The use of computer techniques in the correlation of biological activity with substrate physical-chemical properties has received much attention in the area of medicinal chemistry. The use of these techniques, denoted Quantitative Structure Activity Relationships (QSAR), were developed mostly by Hansch and his coworkers eind have been reviewed by Tute te), Purcell et. al. (9) and Dunn (10). These techniques were utilized by Greenberg (1 l) ln the correlation of odor threshold and suprathreshold data with Log P, the log (n-octanol/water partition coefficient). In the same study it was reported that steric and polar effects as measured by the Taft Steric and Polar Constants poorly correlated with odor intensity data. 

Quantitative structure-activity relationships for fathead minnow Pimephales promelas) LC50 data were developed. As others have observed, log toxicity and log octanol/water partition coefficent (log P) are linearly related for alcohols (n = 20), alkyl ketones (n = 14), alkyl esters (n = 16), and alkyl nitriles (n = 8). When the sums of Taft sigma constants for the substituents of the most anionic carbon in each chemical structure were included in the regression of log LC50 versus log P, the coefficient of determination (r ) improved from 0.84 (for log P only) to 0.92 for alcohols, from 0.82 to 0.92 for ketones, from 0.77 to 0.91 for esters, and from 0.15 to 0.94 for nitriles. The r for the sum of Taft sigma constants versus LC50 for each class was less than 0.17. When the sum of a, was used instead of Taft sigma constants similar results were obtained. 

Quantitative structure-activity relationships, fathead minnow, Pimephales promelas, Taft sigma constants, octanol/water partition coefficients, ketones, nitriles, alcohols, esters. 

Chemometric methods are very useful allowing for predictions of chemical properties. Quantitative structure activity relationships (QSAR) are used in many modern chemical softwares to give a very decent calculated value for chemical properties such as molar volume, boiling point, acidity constant, or octanol/water partition coefficient [42]. The molecule is seen as an association of fragments, each of which contributing to the overall property [43],... 

The history of quantitative structure-activity relationships dates back to the last century, when Crum-Brown and Fraser in 1865 postulated that there ought to be a relationship between physiological activities <1> and chemical structures C. Later, Richet correlated toxicities with aqueous solubility. Around 1900, Meyer and Overton found linear relationships between the narcotic potencies of organic compounds and their partitioning behavior. In the mid-1930s, Hammett defined a reaction constant p to describe the reactivity of aromatic systems R, expressed by rate constants k (or equilibrium constants K) and a parameter o to describe the electronic properties of aromatic substituents X (1 equation 1) (see Linear Free Energy Relationships (LFER)) ... 

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