Hansch approach

This section includes veterinary applications. The antiviral, bactericidal, and antimicrobial applications of 2-aminothiazoles and 2-imino-4-thiazolines are summarized in Table VI-7. They show a marked anti-trichonomicidal activity, which has even been quantitatively measured by the Hansch approach (797). The antiparasitic action of these compounds has been investigated for some compounds and is summarized in Table VI-8 interesting results were obtained with aminotrozal (1348). 

P.N. Craig, Comparison of the Hansch and Free-Wilson approaches to structure-activity correlation, In Biological Correlations — The Hansch Approach (R.F. Gould, Ed.). Advances in Chemistry Series, No. 114. American Chemical Society, Washington DC, 1972, pp. 115-129. P.N. Craig, Interdependence between physical parameters and selection of substituent groups for correlation studies. J. Med. Chem., 14 (1971) 680-684. 

A classical Hansch approach and an artificial neural networks approach were applied to a training set of 32 substituted phenylpiperazines characterized by their affinity for the 5-HTiA-R and the generic arAR [91]. The study was aimed at evaluating the structural requirements for the 5-HTiA/ai selectivity. Each chemical structure was described by six physicochemical parameters and three indicator variables. As electronic descriptors, the field and resonance constants of Swain and Lupton were used. Furthermore, the vdW volumes were employed as steric parameters. The hydrophobic effects exerted by the ortho- and meta-substituents were measured by using the Hansch 7t-ortho and n-meta constants [91]. The resulting models provided a significant correlation of electronic, steric and hydro-phobic parameters with the biological affinities. Moreover, it was inferred that the... 

Objectives Optimize biological activity of drugs Find new active lead compounds Characteristics Response in isolated systems Effects are specific and well defined Specific mechanism of action Receptor is known in most cases Techniques Hansch Approach Multivariate Analysis Computerized molecular modeling Estimate rates of fate processes Analyze Processes Whole organism response Net effects (mortality growth, etc.) Specific nonspecific mechanisms Receptor unknown in most cases Hansch Approach Multivariate Analysis Molecular modeling not applied... 

The information contained in karma s knowledge bases is based upon quantitative structure-activity relationships (QSAR), kinetic data, and structural chemistry. The combination of QSAR and kinetic data allows for the study of enzyme-ligand interactions. The Hansch approach to QSAR, based on a set of congeners, states ... 

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. 

To achieve these various best fits, statistical methods are employed. A regression analysis of the effects of various substituents on a molecule using the Hansch approach... 

Other problems with the Hansch method are that biological systems are often too crude as models for its application, or the electronic effects operative in a drug molecule are not sufficiently understood or precise. Finally, the method requires considerable time and expense, even in the hands of an expert. Difficulties notwithstanding, the Hansch approach took both chemists and pharmacologists out of the dark age of pure empiricism and allowed them to consider simultaneously the effects of a large number of variables of drug activity—a feat unattainable with classical methods. 

The Free-Wilson method of deriving quantitative structure-activity-relationships 101 uses implicit representations of physico-chemical properties and there are also numerous examples where indicator variables have been successfully included in the Hansch approach. 

In recent years, quantitative procedures have been developed for the structure-activity correlation studies of biologically active compounds. Among them, the Hansch approach has been most widely and effectively used and sometimes successfully applied to design novel compounds of potent activity. 

When the Hansch approach was initiated, the correlation of the biological activity (1/C C is the equieffective concentration or dose) with structural parameters was analyzed using Eq. 1,... 

Here k f k2f and kare microscopic ionization constants defined in section 4.6. From this it was possible to calculate and plot variation in Dnoh with pH for pentazocine as shown in Figure 2. The fourth partition coefficient was obtained by structural group contribution to the measured partition coefficient of a reference compound (morphine). This was done following the Hansch approach. 

Several SARs and QSARs have been derived from data on antineoplastic activity as well as for MDR-reversing activity. The Hansch approach, Free-Wilson, and neural network analysis have been applied. The importance of lipophilicity, molar refractiv-ity (MR), and charge for the description of activity is common to all derived relations. 

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 ... 

Based on the earlier work of Meyer and Overton, who showed that the narcotic effect of anesthetics was related to their oil/water partition coefficients, Hansch and his co-workers have demonstrated unequivocally the importance of hydrophobic parameters such as log P (where P is, usually, the octanol/water partition coefficient) in QSAR analysis.28 The so-called classical QSAR approach, pioneered by Hansch, involves stepwise multiple regression analysis (MRA) in the generation of activity correlations with structural descriptors, such as physicochemical parameters (log P, molar refractivity, etc.) or substituent constants such as ir, a, and Es (where these represent hydrophobic, electronic, and steric effects, respectively). The Hansch approach has been very successful in accurately predicting effects in many biological systems, some of which have been subsequently rationalized by inspection of the three-dimensional structures of receptor proteins.28 The use of log P (and its associated substituent parameter, tr) is very important in toxicity,29-32 as well as in other forms of bioactivity, because of the role of hydrophobicity in molecular transport across cell membranes and other biological barriers. 

Gould, R.G.E. Biological Correlations - The Hansch Approach. Advances in Chemistry, 1972,114, The American Chemical Society. 

In Biological Correlations—The Hansch Approach Van Valkenburg, W. Advances in Chemistry American Chemical Society Washington, DC, 1974. 

The background supporting the versatility of the Hansch approach is that it is in fact an extrathermodynamic approach to drug action. The information on the structure-activity relationship of various kinds of drugs is expressed as equations which provide a convenient way for comparative studies with simpler and similar model reactions to elucidate the mechanism of overall drug action without microscopic knowledge of complex processes occurring in vivo. 

---