STRUCTURE-ACTIVITY-RELATIONSHIPS BETWEEN ANTIBACTERIAL ACTIVITIES ANDPHYSICOCHEMICAL PROPERTIES OF SULFONAMIDES

Relationships between the antimicrobial activities of sulfonamides and physicochemical properties including the acid dissociation constant ( pK(a)) and the hydrophobicity constant (pi) were determined. The minim al inhibitory concentrations (MIC) of sulfonamides against Actinobacil lus pleuropneumoniae, a gram-negative veterinary pathogen, were used. High performance liquid chromatography was applied for the determinati on of the electronic and hydrophobic parameters. Empirically determine d relationships pointed out the dominant role of the degree of ionizat ion on the antimicrobial activity. The data indicate that hydrophobic properties of sulfonamides, characterized by pi, are of minor importan ce for the in vitro antibacterial activity. Because of the restricted pK(a) range (4.9-7.7) it could not be established whether the relation ship between pK(a) and activity was linear or bilinear. Whenever o,m-d isubstituted sulfonamides were included correlations decreased substan tially. Relationships based on multicompartment equilibrium models wer e derived and indicated a bilinear relation between pK(a) and MIC. Mod el-based equations showed that the antibacterial activity was governed by the extracellular ionic concentration of the sulfonamides whenever different intra and extracellular pH values were assumed in the equil ibrium model. The antimicrobial activities of the sulfonamides against gram-positive organisms were also related to the degree of ionization of the sulfonamides in the agar medium.