Synthesis and structure-activity relationships of some 4-substituted pyrazole and isoxazole inhibitors of liver alcohol dehydrogenase ; The use of molecular connectivity in the multivariate classification of drug molecules Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/sq87bx54n

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  • In a two part thesis, studies were made of two different types of structure-activity relationships. The first part consists of the synthesis and biological evaluation of a number of 4-substituted pyrazoles and isoxazoles as inhibitors of liver alcohol dehydrogenase. In an effort to better define the steric and electronic effects of substituents, the inhibitory potencies of the compounds were determined in vitro, and these were correlated with the lipophilicity parameter [superscript pi] and with several steric and electronic substituent constants. Lipophilicity showed the most significant relationship with activity. Electronic terms were less significant, but a consistently negative slope coefficient for these terms suggests that a positive charge develops on the pyrazole ring during interaction with LADH, which is not consistent with a previously proposed anionic intermediate. In the second part of the thesis, retrospective research was performed to determine the usefulness of fragment and whole-molecule molecular connectivity (MC) indices in the multivariate classification of drug structures. Initially, using a template method of position assignment, a number of diphenylmethyl-based compounds from a previous study were examined using linear and quadratic discriminant analysis. Relative molar refraction was compared with several fragment MC values as descriptor indices. First order fragment MC was found to be the most useful descriptor of those examined, and this was verified in a second study using a number of steroids classified into five therapeutic categories. In a third study, these steroids were examined using a number of pattern recognition techniques. It was concluded that there was no advantage to the use of pattern recognition techniques over discriminant analysis, especially since stepwise variable selection is available in the latter. Finally, using a composite of the structures that had been studied, a comparison was made between the recently introduced SIMCA method of modelling and classification, and conventional discriminant analysis. Simple and valence whole-molecule MC indices were used as descriptors to avoid the problems of position assignment. The original sample classification results were similar using both techniques. When a holdout-by-four method of validation was performed, linear discriminant analysis gave better results than either SIMCA or the quadratic discriminant function. This reflects the effects of small sample sizes on the latter two methods. A comparison of the canonical discriminant function values and the principal component scores from SIMCA as predictors of the quantitative potencies of a number of androgens was made, and higher correlations were found with the discriminant function values. This evidence again suggests that no advantages are gained by using techniques other than discriminant analysis, although more experience with pattern recognition methods is necessary to be certain of this conclusion.
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