Abstracts Chemistry

A quantitative structure activity relationships study of antiinfectives based on the nalidixic acid structure

by Yupei Yu

Nalidixic acid and its derivatives act through inhibition of bacterial DNA gyrase activity. Recently there have been a series of papers reporting the antibacterial activity against three different types of bacteria (S. aureus, E. coli and P. aeruginosa) by a series of 1,4-dihydro-4-oxoquinoline (or 1,8-naphthyridine) 3-carboxylic acids. Consistent biological data is available for a quantitative structure activity relationships (QSAR) study on three sets of compounds totaling over 120 potential antibacterial agents. The two most frequently used models in quantitative structure activity relationship are the linear free energy relationships (LFER) regression model developed by Hansch and the additive substituent or de novo model developed by Free and Wilson. The object of this research is to apply the Hansch and Free-Wilson statistical models to a series of antibacterial analogues of pyridone carboxylic acids. The Hansch model mostly uses physicochemical parameters as the independent variables to predict and explain the biological activity. In this project the partition coefficients, Log P calculated by the fragment (f) method, molar refractivity (MR), and STERIMOL (L, B1 and B5) parameters were used in a LFER analysis. The Free-Wilson model measures the contribution of a specific substituent to the biological activity. Both the standard de novo model and a mixed model using physicochemical parameters and Free- Wilson's indicator variables as independent variables were examined in this research. There are three locations on the molecule in which substituents are varied. These are position 1, 6 and 7. Both the LFER and de novo models show position 7 to have the most variance. In other words, position 1 tends to be insensitive to changes in substituents. Position 6 requii.es a fluorine to maximize activity. Subsets of compounds in which the substituent were varied only at position 7 were examined. In general only specific substituents contribute significantly to antibacterial activity.