Anti-Toxoplasma gondii activities and structure-activity relationships of novel fluoroquinolones related to trovafloxacin.

Eleven novel fluoroquinolones closely related to trovafloxacin were evaluated for their in vitro activity against Toxoplasma gondii, and their structure-activity relationships were examined. The 50% inhibitory concentration (IC50) of trovafloxacin against T. gondii was 2.93 microM; the IC50 of the 11 analogs ranged from 0.53 to 14. 09 microM. Six analogs had IC50s lower than that of trovafloxacin. Examination of the structure-activity relationships of the compounds revealed that addition of a -CH3 at C-5 of the 1,8-naphthyridone ring, at C-2 of the azabicyclohexane ring, or on the -NH2 at the 6 position of the azabicyclohexane ring resulted in a four- to sixfold increase in activity. Moreover, replacement of 2,4-difluorophenyl by cyclopropyl at N-1 of the 1,8-naphthyridone ring increased activity twofold, and moving the -NH2 one atom further away from the azabicyclohexane ring decreased activity. There was no difference between the naphthyridone and quinolone analogs. These results indicate that structure-activity studies of compounds related to drugs active against T. gondii may be useful in producing compounds with more potent activities against the parasite.

The chemistry and biological profile of trovafloxacin.

The fluoroquinolone antibacterials are noted for their activity after oral administration and potent activity against Gram-negative pathogens. Trovafloxacin (CP-99,219) is a new quinolone antibacterial characterized by a novel 3-azabicyclo[3.1.0]hexyl substituent at the C-7 position, which was discovered in the course of a programme targeting improved activity compared with ciprofloxacin against Gram-positive aerobic organisms and anaerobes, as well as an extended elimination half-life. An overview of the chemical properties of trovafloxacin is given. Trovafloxacin exhibits excellent potency against Gram-positive organisms and anaerobes, while retaining the potent Gram-negative activity of ciprofloxacin. Its pharmacokinetic properties in humans have been shown to be compatible with a once-daily dosing regimen. The combined spectrum and pharmacokinetics of trovafloxacin have been demonstrated to result in excellent efficacy in both animal models of infections and human clinical trials. Phase II and Phase III programmes have been completed.

Metabolism and excretion of trovafloxacin, a new quinolone antibiotic, in Sprague-Dawley rats and beagle dogs. Effect of bile duct cannulation on excretion pathways.

The excretion and metabolism of trovafloxacin was investigated after administration of a single oral dose of [14C]trovafloxacin to Sprague-Dawley rats and beagle dogs. The bile was the major route of excretion in rats (59% of the dose). Trovafloxacin was extensively metabolized in this species, and only 3% of the dose was excreted unchanged. Glucuronidation and acetylation were the major metabolic pathways involved in the elimination, and no oxidative metabolites were detected in rats. In dogs, 97.6 and 2.7% of the dose was recovered in feces and urine, respectively, in 72 hr. However, excretion studies in bile duct-cannulated dogs revealed that 28.2% of the radioactivity was recovered in bile, whereas 45.6% was in urine. This suggested that bile duct cannulation had affected the disposition of trovafloxacin. Analysis of bile and urine of bile duct-cannulated dogs by LC/MS/MS indicated that glucuronidation was the major metabolic pathway in dogs as well. Two novel metabolites were identified in the bile of this species. One was confirmed as a pyrroline analog of trovafloxacin (M7), and the second was tentatively identified as the hydroxycarboxylic acid analog (M6). The differences in metabolism of trovafloxacin in the bile duct-cannulated and noncannulated dogs were investigated by comparison of the metabolite profiles in urine and feces of these animals. Although the metabolites in urine were similar, the extracts of fecal samples obtained from noncannulated animals revealed the presence of N-acetyltrovafloxacin (M3). Incubation of trovafloxacin with cecal contents of dogs under anaerobic conditions suggested the involvement of intestinal microflora in the formation of this metabolite. Metabolite M3 was absent from fecal extracts of bile duct-cannulated dogs, suggesting that surgery had affected the metabolism of trovafloxacin by gut microflora.

In vitro activity of CP-99,219, a novel 7-(3-azabicyclo[3.1.0]hexyl) naphthyridone antimicrobial.

The in vitro activity of CP-99,219 was compared with that of ciprofloxacin and sparfloxacin against 814 clinical bacterial isolates using a microdilution method with brain-heart infusion broth. CP-99,219 was the most potent agent tested against methicillin-resistant, ciprofloxacin-susceptible staphylocci (minimum inhibitory concentration [MIC]90 < or = 0.25 microgram/ml). CP-99,219 was 32-fold and fourfold more potent than ciprofloxacin and sparfloxacin, respectively, against Streptococcus pneumoniae, including strains resistant to penicillin G and erythromycin (MIC90 < or = 0.25 microgram/ml). CP-99,219 was also the most potent agent tested against S. pyogenes and Enterococcus faecalis (MIC90 < or = 0.5 microgram/ml). The activity of CP-99,219 against Enterobacteriaceae was comparable to that of sparfloxacin, with 90% of Escherichia coli, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Citrobacter freundii, C. diversus, Helicobacter pylori, and K. oxytoca being inhibited by < or = 0.5 microgram/ml. Serratia marcescens, Morganella morganii, and Pseudomonas aeruginosa were less susceptible, with MIC90 values to CP-99,219 of 4, 2, and 2 micrograms/ml, respectively. The MIC90 for Bacteroides fragilis was 0.39 microgram/ml for CP-99,219 compared with 12.5 micrograms/ml for ciprofloxacin. CP-99,219 was highly bactericidal at 1 x to 4 x MIC against both Gram-positive and Gram-negative organisms; its activity was similar in nutrient, trypticase soy, and cation-supplemented Mueller-Hinton broths. The spectrum and potency observed with CP-99,219 warrant further testing with this novel quinolone.