Hansch’s correlations

DOUBLE-RECIPROCAL PLOT HANSCH CONSTANT HANSCH EQUATION HANSCH S CORRELATION ANALYSIS Hapten,... 

Quantitative structure-activity relationships, HANSCH S CORRELATION ANALYSIS QUANTASOME QUANTUM... 

Several studies have shown that sorption of various organic compounds on solid phases could be depicted as an accumulation at hydrophobic sites at the OM/water interface in a way similar to surface active agents. In addition Hansch s constants [19,199-201], derived from the partition distribution between 1-octanol and water, expressed this behavior better than other parameters. Excellent linear correlations between Koc and Kow were found for a variety of nonpolar organic compounds, including various pesticides, phenols, PCBs, PAHs, and halogenated alkenes and benzenes, and various soils and sediments that were investigated for sorption [19,76,80,199-201]. 

In 1993, Martin and colleagues performed a follow-up study on the same 15 compounds using CoMFA. CoMFA does not produce a simple equation in the manner of Hansch analysis, but CoMFA does calculate activities for the training set compounds. Comparing the predicted and experimental activities allows determination of the model s correlation coefficient. The CoMFA performed by Martin gave an r-value of 0.96. Martin s CoMFA model accounted... 

Hydrophobicity of an inhibitor and critical micelle concentrations of the inhibitor in forming micelles have been found60 to play a significant role in the case of substituted imidazoles, imidazolines and fatty amines and these correlations do not take into account the electronic interactions. This correlation is based on Hansch s model of drug-receptor interactions based on transport of drug/inhibitor to the site followed by interaction at the site. 

The electron-releasing groups located at the end of the Table 15 present also a good correlation with the values predicted for the OH and OMe, —0.31 and —0.34, are consistent with the larger nucleophilic character expected for the methoxy group with respect to the hydroxyl one. Note however that the [Pg.186]

Hansch s reevaluation of the earlier QSAR study of in vivo data (108)resulted in Equation 5.16 for the pentylenetetrazole test. In contrast to Equation 5.9), which shows no role for hydro-phobic effects. Equation 5.16 is positively correlated with both hydrophobicity and steric effects cf the C7 and C2 substituents as well as with qo (chargeon the carbonyl oxygen). 

The data do not correlate well with Hansch s n parameters and it may be concluded that the catalysis does not involve a significantly apolar interaction between the amide backbone of the substrate and the active sub-site, pp Reference to the original literature (reference 38 of Chapter 2) indicates that correlates reasonably well with Pg, a parameter measuring polarisability this is consistent with the postulate derived from structural data that there is hydrogen-bonding between the amide of the substrate and the binding sub-site of the active site. 

Several substituent constants, including the Taft Eg, have been employed by Hamor and Lien in the study of anticonvulsant activities of alkyl esters of 2-sul amoylbenzoic acid against maximal electroshock and against strychnine-induced convulsions. The steric substituent constant, E, the electronic substituent constants, a and o, ana log P calculated from Hansch s ir values were examined for correlation with biological response. For antistrychnine action, the best... 

In these equations, Dmax is the larger of the summed values of STERIMOL parameters, Bj, for the opposite pair 68). It expresses the maximum total width of substituents. The coefficients of the ct° terms in Eqs. 37 to 39 were virtually equal to that in Eq. 40. This means that the a° terms essentially represent the hydrolytic reactivity of an ester itself and are virtually independent of cyclodextrin catalysis. The catalytic effect of cyclodextrin is only involved in the Dmax term. Interestingly, the coefficient of Draax was negative in Eq. 37 and positive in Eq. 38. This fact indicates that bulky substituents at the meta position are favorable, while those at the para position unfavorable, for the rate acceleration in the (S-cyclodextrin catalysis. Similar results have been obtained for a-cyclodextrin catalysis, but not for (S-cyclodextrin catalysis, by Silipo and Hansch described above. Equation 39 suggests the existence of an optimum diameter for the proper fit of m-substituents in the cavity of a-cyclodextrin. The optimum Dmax value was estimated from Eq. 39 as 4.4 A, which is approximately equivalent to the diameter of the a-cyclodextrin cavity. The situation is shown in Fig. 8. A similar parabolic relationship would be obtained for (5-cyclodextrin catalysis, too, if the correlation analysis involved phenyl acetates with such bulky substituents that they cannot be included within the (5-cyclodextrin cavity. 

A table of correlations between seven physicochemical substituent parameters for 90 chemical substituent groups has been reported by Hansch et al. [39]. The parameters include lipophilicity (log P), molar refractivity MR), molecular weight MW), Hammett s electronic parameters (a and o ), and the field and resonance parameters of Swain and Lupton F and R). 

As noted by the original authors (Dorovska et al., 1972), and cited by Fersht (1985), there is an excellent linear correlation between log/ccat/KM and the Hansch hydrophobicity parameters (v) of the side chains (Fig. 9, A), except for the two branched side chains (valine and isoleucine residues). However, since the ku values for the esters do vary somewhat (Table A6.8), the values of pKrs do not correlate as strongly with ir (Fig. 9, B). Moreover, the plot shows distinct curvature which probably indicates the onset of a saturation effect due to the physical limits of the Sj binding pocket, adjacent to the enzyme s active site. Still, the points for valine and isoleucine deviate below the others, suggesting that the pocket has a relatively narrow opening. 

There is a long history of efforts to find simple and interpretable /i and fi functions for various activities and properties (29, 30). The quest for predictive QSAR models started with Hammett s pioneer work to correlate molecular structures with chemical reactivities (30-32). However, the widespread applications of modern predictive QSAR and QSPR actually started with the seminal work of Hansch and coworkers on pesticides (29, 33, 34) and the developments of various powerful analysis tools, such as PLS (partial least squares) and neural networks, for multivariate analysis have fueled these widespread applications. Nowadays, numerous publications on guidelines, workflows, and... 

For substituted alcohols reacting with hydroxyl radicals, the least substituted alcohol, methanol, was used as a reference compound for Hammett correlation analysis. The o values were taken from Hansch et al. (1995) and rate constants were taken from the U.S. Department of Commerce (USDOC, 1977). These values are believed to be the most accurate rate constants in... 

Hammett s equation was also established for substituted phenols from the elementary hydroxyl radical rate constants. The Hammett resonance constant was used to derive a QSAR model for substituted phenols. The simple Hammett equation has been shown to fail in the presence of electron-withdrawing or electron-donating substituents, such as an -OH group (Hansch and Leo, 1995). For this reason, the derived resonance constants such as o°, cr, and o+ were tested in different cases. In the case of multiple substituents, the resonance constants were summed. Figure 5.24 demonstrates a Hammett correlation for substituted phenols. The least-substituted compound, phenol, was used as a reference compound. Figure 5.24 shows the effects of different substituents on the degradation rates of phenols. Nitrophenol reacted the fastest, while methoxyphenol and hydroxyphenol reacted at a slower rate. This Hammett correlation can be used to predict degradation rate constants for compounds similar in structure. 

In a study of analogues of the antibiotic metronidazole (12.a, R = OH), antimicrobial activity against T. vaginalis (log AA) was correlated to activation free energy of electroreduction (AG) and lipophilicity (log P). Both AG and log P are whole molecule parameters. Create a Hansch equation based on these parameter values and following activity data. Interpret the effect of each parameter on antimicrobial activity. (Chien, Y. W., Mizuba, S. S. Activity-Electroreduction Relationship of Antimicrobial Metronidazole Analogues. J. Med. Chem. 1978, 21, 374—380.)... 

Tute, M.S. (1971) Principles and practice of Hansch analysis A guide to structure-activity correlation for the medicinal chemist. Adv. Drug Res. 6, 1-77. 

Isnard, P, Lambert, S. (1989) Aqueous solubility/n-octanol water partition coefficient correlations. Chemosphere 18, 1837-1853. Iwasa, J., Fujita, T., Hansch, C. (1965) Substituent constants for aliphatic functions obtained from partition coefficients.. /. Med. Chem. 8, 150-153. 

Hansch C, Fujita T (1964) r-s-p analysis. A method for the correlation of biological activity and chemical structure. J Am Chem Soc 86 1616-1626. 

This approach to estimating C does not require the water solubility be known or determined expirimentally. Several laboratories have studied the relationship between the water solubility of a compound and its log P (octanol) value. Hansch, et al. (36) showed that for 156 organic liquids, the molar water solubilities (S ) were correlated to P by equation 21a. The correlation coefficient was increased to as high as 0.99 by segregating compounds by chemical... 

The second equation is often applicable to equilibrium situations such as those found in vitro. Sometimes, different dependencies on tt are found for substituents in different parts of the molecule. The hydrolysis rates of substituted phenyl / -D-glucosides by emulsin, for instance, have been shown by Hansch (I) to depend on w for the para substituents but not on tt for the meta substituents. Some of Baker s results (2) on the 5,6-disubstituted-2,4-diaminopyrimidines as inhibitors of dihydrofolate reductase can be correlated with tt only by choosing tt for the most lipophilic of the two substituents (3). Only a part of the molecule need be desolvated on combining with the receptor. 

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