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Reprinted with permission from Hansch, C., and Leo, A. J.: Substituent Constants for Correlation Analysis in Chemistry and Biology. New York, John Wiley & Sons, 1979.

Reprinted with permission from Hansch, C., and Leo, A. J.: Substituent Constants for Correlation Analysis in Chemistry and Biology. New York, John Wiley & Sons, 1979.

Nevertheless, medicinal chemists can use information from extensive tables of physicochemical parameters to minimize the number of substituents required to find out if the biological response is sensitive to electronic, steric, and/or partitioning effects.5 This is done by selecting substituents in each of the numerical ranges for the different parameters. In Table 2.6, there are three ranges of B values (-1.23 to -0.55, -0.28 to 0.56, and 0.71 to 1.55); three ranges of MR values (0.92-2.85, 5.02-8.88, and 10.30-14.96); and two main clusters of $ values, one for the aliphatic substituents and the other for the halogens. In the ideal situation, substituents are selected from each of the clusters to determine the dependence of the biological response over the largest possible variable space. Depending on the biological responses obtained from testing the new compounds, it is possible to determine if lipophilicity (partitioning), steric bulk (molar refraction), or electron-withdrawing/donating properties are important determinants of the desired biological response.

With this background in mind, two examples of QSAR equations taken from the medicinal chemistry literature are presented. A study of a group of griseofulvin analogs showed a linear relationship (Eq. 2.15) between the biological response and both lipophilicity (log P) and electronic character (^).6 It was suggested that the antibiotic activity may depend on the enone system facilitating the addition of griseofulvin to a nucleophilic group such as the SH moiety in a fungal enzyme.

Gri seofulvin: R = R1 = R2 = OCH3; R3 = CI; X = H

A parabolic relationship (Eq. 2.16) was reported for a series of substituted acetylated salicylates (substituted aspirins) tested for anti-inflammatory activity.7 A nonlinear relationship exists between the biological response and lipophilicity, and a significant detrimental steric effect is seen with substituents at position 4. The two sterimol parameters used in this equation were L, defined as the length of the substituent along the axis of the bond between the first atom of the substituent and the parent molecule, and B2, defined as a width parameter. Steric effects were not considered statistically significant at position 3, as shown by the sterimol parameters for substituents at position 3 not being part of Equation 2.16. The optimal partition coefficient (log Po) for the substituted aspirins in this assay was 2.6. At the same time, increasing bulk, as measured by the sterimol parameters, decreases activity.

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