QSAR and Molecular Modelling for a Series of Isomeric X‐Sulfanilamido‐1‐phenylpyrazoles

The influence of large substituents in o‐, m‐ and p‐positions of the phenyl ring of isomeric 3‐, 4‐ and 5‐sulfanilamido‐1‐phenylpyrazoles on their inhibitory effect against E.coli derived dihydropteroic acid synthase and whole cell E.coli has been studied. According to their pKa values, the 3‐ and 5‐series show high antibacterial activity while the 4‐series displays feeble inhibitory activity. In the 3‐series the variation in MIC is explained by differences in pKa (Hammett σ) and molecular weight (MW) or substituent surface respectively, whereas in the 5‐series steric effects of substituents in the o‐position of the 1‐phenyl ring and MW describe the differences in whole cell activity. In the cell‐free system the inhibitory activity depends for the 3‐series solely on pKa or Hammett σ, respectively, and in the 5‐series, where the derivatives are almost completely ionized, the variation is solely explainable by the steric effect of the substituents in o‐position. The steric effect of o‐substituents in the 5‐series has been studied and explained by NMR‐ and molecular modelling techniques. The observed differences in electronic effects of substituents comparing the 3‐ and 4‐series with the 5‐series could be explained by the results of quantum chemical calculations.