p-Aminobenzoic acid derivatives. Mode of action and structure-activity relations in a cell-free system (Escherichia coli)

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Abstract
The agonistic and antagonistic effects of nuclearly substituted p-aminobenzoic acids (PABA) on the folate-synthesizing system of E. coli were studied in whole cell and cell-free systems. All studied derivatives form dihydropteroic acid analogs in the presence of a cell-free folate-synthesizing enzyme system. A TLC system was elaborated to determine the rate of analog formation in the cell-free system. Physicochemical parameters of the PABA derivatives, such as pKa, .pi. and Rm values, were determined. These values were used in a structure-activity analysis which revealed that the rate of analog formation in the absence of PABA is independent of the lipophilic properties. Ionization may be the decisive factor for the incorporation. As all studied PABA derivatives are totally ionized under the experimental conditions, the rates of analog formation are very similar, with the exception of compounds bearing bulky groups in the 2 position. The variance in inhibitory power may be due to differences in the ability of the analogs to serve as metabolites or due to competition with PABA.

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