Syntheses and biological activities of new N-1-aryl substituted quinolone antibacterials

A series of quinolones with a systematically varied substitution at the phenyl ring at N1 has been synthesized. Three lipophilicity descriptors (log K, log P, R(m)) and the pK(a) values have been determined as well as the microbiological activity. The MIC values for eight different strains of three Gram-positive and three of DNA supercoiling (IC90 and IC100) were determined. From a principal component and a QSAR analysis relationships between the antibacterial activity concerning the whole-cell system and electronic properties as well as the length of the substituents at the phenyl rings could be derived. The activity in a cell-free system was governed by the lipophilicity and width of the substituents. It is speculated that the quinolones take a defined place in the DNA gyrase-DNA complex which is characterized by polar amino acids. This is in agreement with findings from studies of mutant gyrases.