Syntheses and Biological Activities of New N₁‐Aryl Substituted Quinolone Antibacterials

Abstract

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, Rm) and the pKa values have been determined as well as the microbiological activity: The MIC values for eight different strains of three Gram-positive and three Gram-negative species and the inhibitory concentrations of DNA supercoiling (IC90 and IC100) were determined. From a principal component and a QSAR analysis relationships between 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 the 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.

Plasma Protein Binding of Gyrase Inhibitors

“…In addition, the octanol/water partition coefficient (log D) characterizing the overall lipophilicity of a drug was determined by the standard procedure already reported by us and other groups. 8,16,17 The log D values are in a range of -2.1 and +0.6, with the low values indicating a high water solubility (at pH 7.4) and the high values characterizing a certain degree of lipophilicity. Gyrase inhibitors of the first, second, and third generation are at both ends of the range.…”

“…MaterialssNalidixic acid and rosoxacin were supplied from Sanofi Winthrop GmbH (Mü nchen, FRG), norfloxacin was from MSD (Mü nchen, FRG), oxolinic acid and enoxacin were from Gödecke AG (Freiburg, FRG), ciprofloxacin and enrofloxacin were from Bayer AG (Leverkusen, FRG), trovafloxacin was from Pfizer GmbH (Karlsruhe, FRG), fleroxacin was from Hoffmann La-Roche AG (Grenzach-Wyhlen, FRG), pipemidic acid, pefloxacin, and sparfloxacin were from Rhone-Poulenc Rorer GmbH (Köln, FRG), ofloxacin and levofloxacin were from Hoechst AG (Frankfurt, FRG), difloxacin was from Abbott (Abbott Park, IL), rufloxacin was from Mediolanum (Milano, Italy), and cinoxacin was from Lilly Deutschland GmbH (Giessen, FRG). Methylciprofloxacin was synthesized according to a method reported by Jü rgens et al 8 starting off with 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylate. The structures are displayed in Scheme 1.…”

Effects of fluoroquinolones on HERG channels and on pancreatic β-cell ATP-sensitive K+ channels

“…Sparfloxacin was a gift from RhonePoulenc Rorer GmbH (Köln, Germany). Syntheses of compounds C1-C4 were performed according to Jürgens et al (1996). A stock solution of 1 mM lomefloxacin was prepared either in solution (B) (for inside-out experiments) or in solution (E) (for whole-cell experiments) and diluted to the final concentrations.…”

Defluorinated Sparfloxacin as a New Photoproduct Identified by Liquid Chromatography Coupled with UV Detection and Tandem Mass Spectrometry

“…Synthesis of the reference substance, 8-amino-1-cyclopropyl-1,4-dihydro-7-(2,6-dimethyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, compound 10. The reference substance, compound 10, has been synthesized by the methods described in the literature (3,11) (Fig. 1).…”