Hansch improvement

The correlations between chemical descriptors of molecular properties and biological activity, especially the activity of herbicides and/or plant growth regulators has been described (12). Several alternatives or improvements on the Hansch-Fujita QSAR system have been developed (13—15). 

Hansch analysis marked the breakthrough of QSAR. The method was soon extended with additional parameters with the aim of improving the fit between biological and physicochemical data and for the prediction of drugs with optimal... 

The procedure takes as input parameters the measured (or calculated) pKa and the measured (or calculated) octanol-water partition coefficient, log P. The latter parameter is used to estimate the intrinsic solubility So, using the Hansch-type expression [38], log So = 1.17 — 1.38 log P, or an improved version for ionizable molecules of moderate lipophilicity (Fig. 6.6) ... 

The measurement of the solubility of drugs in polar and non-polar media is very important in the pharmaceutical field. One method proposed to describe this solubility is the partition coefficient between octanol and water. The mathematical calculation of an octanol-water partition coefficient from values for functional groups was first proposed by Hansch et al. as Hansch s n constants,1 and was later developed by Rekker as hydrophobic fragmental constants (logP).2 This method was further improved by the use of molecular connectivities.17 The prediction of logP values can be performed by either a computer program or by manual calculation. For example, approximate partition coefficients (log P) have been calculated by Rekker s method ... 

Hansch analysis is useful not only for drug discovery. A study of insecticides and related nonpolar compounds has shown that the bioconcentration of these compounds (log BC) in trout muscle is related to log P. Create a Hansch equation based on the following data. Does including a (log P)2 term improve the fit Is this surprising Explain. (Neely, W. B., Branson, D. R., Blau, G. E. Partition Coefficient to Measure Bioconcentration Potential of Organic Chemicals in Fish. Environ. Sci. Technol. 1974,8, 1113-1115.)... 

These efforts were guided by the study of quantitative structure-activity relationships (QSAR) following the Hansch approach. In this method linear free-energy related and other electronic, hydrophobic, and steric substituent constants are used for a quantitative analysis of the possible ways in which substituents may modulate bioactivity in a congeneric series. In the QSAR studies of benzoylphenyl ureas the electronic Hammett a-constants and the hydro-phobic Hansch n-constants were used. To measure the steric influences, steric substituent constants of a new type (B1,B2,B3,B4, and L) were applied which had recently been introduced by us and which give improved correlations in comparison with the steric Es constants used in the literature hitherto (21, 22). The constants B- toBj are measures of the widths of substituents in four rectangular directions. The L-constant accounts for the length of a substituent ... 

Since the first analysis by Hansch two significant developments have been made. The first is that a wide range of easily computable molecular descriptors are now available and the second is that many sophisticated techniques have emerged that are a significant improvement over the original linear regression... 

This experimental measurement of the Ha wavelength produced a value of the Rydberg constant with an accuracy that was a tenfold improvement over previous experiments. The value of the Rydberg constant that Hansch and his collaborators obtained was... 

The Hansch-Fujita method, the Free-Wilson theory (described by Craig in Chapter 8), and the molecular orbital theory (described by Kier, Chapter 15) have greatly increased our understanding of the mode of action of many biological chemicals. It has also improved our ability to predict the activity of a variety of chemicals against plant and insect pests and certain pathogenic organisms. 

For reasons discussed below, data points for the 4-SCH3 and 3-SCH3 derivatives were omitted from the fits of Equations 10-12. Hence n, the number of data points included in the fits, equals 13 instead of 15. Examination of Equations 10-12 indicates, however, that even though log (I/LD90) exhibits a fairly strong dependence on <7, the data are not particularly well correlated by the Hansch equation. Addition of r2 and tt terms to Equation 10 raises the percent correlation (r2) from 61 to 67%, but F is decreased and the standard error SE increased in the process. Hence, the correlation is not statistically improved. 

The statistical parameters in Equations 13—15 for the 4-substituted TFMS series members and Equations 16-18 for the 3-substituted compounds demonstrate that the fit of the biological data to the Hansch equation is significantly improved when the TFMS herbicides are separated into two classes (cf. Equations 10-12). Both the 3- and 4-series exhibit a strong dependence not only on o-, but also on tt. For the 4-sub-... 

Methylthio TFMS Derivatives. Data for the meta- and para-substituted methylthio TFMS derivatives (3-SCH3, 4-SCH3) were not included in Hansch structure—activity correlations for the several weed types. This omission was a result of our noting that when herbicidal data for the methylthio derivatives were included in fits, much poorer Hansch correlations were obtained. This was true whether or not the TFMS compounds were separated into meta- and para-derivatives for fitting purposes. It was also true for all weed types examined, in the presence and absence of surfactant. A typical example of the improvement in statistical parameters effected by omitting methylthio points from the data pool is illustrated by the following Hansch correlation of TFMS activity on Foxtail grass in the presence of surfactant. 

Placement of the Parent Compound. Separation of the TFMS herbicides into two classes consisting of meta- and para-substituted derivatives which were fitted separately resulted in significantly improved correlations via the Hansch equation. It was not readily apparent, however, into which of the two herbicidal categories the H-substituted parent com-... 

TFMS derivative in the presence of surfactant (cf. also Figures 2a and 2c). Thus, the loss in Foxtail activity which results from the deleterious effect of surfactant on the pa term in the Hansch equation is compensated by the improved partitioning characteristics (large Bn term) of the 4-methylsulfonyl derivative in the presence of surfactant. The net result is that the overall pre-emergence Foxtail activity is not greatly affected by Tween 80. As illustrated in Table XIII, however, this effect is only apparent since significant changes in both ir and a dependence have taken place. 

Equations (9) and (10) constitute the fundament of all QSAR studies. Since 1964, they have remained essentially unchanged, with the exception of two minor modifications. Improvements resulted from the combination of Hansch equations with indicator variables [22], which may be considered as a mixed Hansch/Free-Wilson model (Eq. (11)) [23], and from the formulation of a theoretically derived nonlinear model for transport and distribution of drugs in a biological system, the bilinear model (Sec. 4 Eq. (30)) [24] ... 

Integrating various factors, namely Taft s steric factor, resonance, inductive, Verloop steric parameters with the partition behaviour of drug molecules Hansch and Fuj ita exploited these principles in determining the establishing quantitative structure-activity relationship (QSAR) of drugs, which has rmdergone a sea change both in expansion and improvement with the help of computer researched softwares. 

Both models remained unchanged over the past three decades. Some improvements resulted from the combination of Hansch equations with indicator variables... 

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