Hansch approach QSAR study using

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 ... 

Srikanth K, Debnath B, Jha T. QSAR study on adenosine kinase inhibition of pyrrolo[2,3-d]pyrimidine nucleoside analogues using the Hansch approach. Bioorg Med Chem Lett 2002 12 899-902. 

Pre-Qsar" Series Development. Potency (Log 1/c) values for the first nineteen pyranenamlnes to be synthesized and tested In the PCA assay, prior to the use of QSAR In this series, appear In part A of Table I. The majority of these derivatives were synthesized in response to a newly proposed (at that time) decision model, the Topllss operation scheme or "tree .Q). Based on the observation that physlcochemlcally-based substituent constants are an aspect of the Hansch approach which is easier for synthetically oriented chemists to assimilate than is regression analysis, Topllss proposed specific sequences of substituted derivatives to be synthesized, with the next choice at each sequential step being governed by whether the preceding compound displayed either Increased, decreased, or unaltered potency. Retrospective studies... 

Approach was used in deriving mechanistic information about odor intensity as well as insight into how this biological activity may be predicted. This paper will first briefly describe the history of QSAR, the QSAR parameters used, and how substituents for QSAR studies are selected. Several examples of the Hansch Approach used in taste and odor quality studies will next be presented. The balance of the paper will deal with the development of quantitative structure odor intensity relationships which will further expand upon the earlier study reported by this author (11). For example, the use of relatively new QSAR steric parameters in correlations with odor intensity data, and correlations of log P with literature odor intensity data determined on animal panels will be presented. This will be followed by conclusions derived from those studies, and areas of future work. 

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. ... 

The criticisms in the previous paragraphs lead to a question If Hansch analysis is of such questionable value, then why has an entire chapter of this textbook been devoted to the subject Despite the fading utility of classical QSAR methods such as Hansch analysis, the logic behind Hansch analysis is invaluable to medicinal chemistry. Synthetic chemists in the pharmaceutical industry intuitively consider the ideas used to construct Hansch equations. Ideas such as electronics, sterics, and lipophilicity underlie traditional SAR approaches in the laboratory. Critical analysis of activity data and emphasis on seeking holes in R-group selection are also fundamental to successful SAR on a lead. Through the study of Hansch analysis, all these crucial ideas are presented in a rational framework that helps demonstrate their relevance. Just as importantly, Hansch analysis provides the foundation for the next generation of QSAR comparative molecular field analysis. 

Roy and Leonard [183] have also presented QSAR models for the HIV-1 RT inhibitory activity of the thiazolidinones listed in Tables 16 and 17 along with some more similar analogues (Table 18) [184-187] using the hydrophobic-ity and molar refractivity, quantum chemical and topological and indicator parameters as descriptors. In this, the 3-pyridyls/phenyls (Tables 16 and 17) and 3-(pyrimidin-2-yls) (Table 18) [186] have become part of the dataset. Additionally, four compounds with the thiazolidin-4-thione nucleus have been included in the dataset. In Fujita-Ban [188] and mixed (Hansch and Fujita-Ban) approaches 7 to 17 descriptor models have been discovered for the cytopathicity effect (EC50) and cytotoxic effect (CC50) of the compounds. The following equations show the minimum descriptor models for each activity from this study. 

In 1962, Hansch, Maloney and Fujita [Hansch, Maloney et al, 1962] published their study on the structure-activity relationships of plant growth regulators and their dependency on Hammett constants and hydrophobidty. Using the octanol/water system, a whole series of partition coefficients was measured and, thus, a new hydrophobic scale was introduced for describing the inclination of molecules to move through environments characterized by different degrees of hydrophilicity such as blood and cellular membranes. The delineation of Hansch models led to explosive development in QSAR analysis and related approaches [Hansch and Leo, 1995]. This approach known with the name of Hansch analysis became and it still is a basic tool for QSAR modeling. 

QSAR Correlation. Statistical quality of QSAR correlation can be employed as a third criterion of commonality of mechanism. This approach can prove very meaningful when coupled with a mechanistic interpretation of the role of molecular descriptors used in the correlation, and with the significance of the slope and intercept. The quality of statistical fit and the interpretation of the parameter or parameters used in the correlation can provide a valuable insight into molecular mechanism. Recently, Hansch analysis has been combined with molecular graphics and modeling studies in which the activities of a series of substrates to an enzyme receptor have been related to the hydrophobic, electronic, and steric requirements for reversible binding... 

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