Quantitative Structure-Time-Activity Relationships (QSTAR): pH-Dependent Growth Inhibition of Escherichia coll by Ionizable and Nonionizable Kojic Acid Derivatives. Part II

The previously published model of the model-based quantitative structure-time-activity relationship (QSTAR) for growth inhibitory activity of nonionizable series of kojic acid (5-hydroxy-2-hydroxymethyl-4H-pyrane-4-one) derivatives against Escherichia coli has been extended for the complete set consisting of 21 nonionizable and 14 ionizable compounds. The inhibitory activity has been characterized by the isoeffective concentrations causing 50%-decrease in the specific growth rate in comparison with the untreated control after the five exposure periods in 7 media differing in their pH values (pH 5.6–8.0). For an acceptable fit of the model to the data the receptor binding of both ionized and nonionized molecules had to be considered and the model modified accordingly. The model describes the toxicity of the tested compounds as an explicit non-linear function of hydro-phobicity, pKa values, the size of the substituent in the position 2, the pH values of the external media, and the time of exposure. The results can be interpreted as follows. Elimination as well as binding to the receptor have been positively influenced by both size of the molecules and ionization. The ionized molecules exhibit about 2.6 × 103 stronger binding to the receptors than their nonionized counterparts. The QSTAR model can be used for rational development of more effective derivatives.