Synthesis, antibacterial activity, and toxicity of 7-(isoindolin-5-yl)-4-oxoquinoline-3-carboxylic acids. Discovery of the novel des-F(6)-quinolone antibacterial agent garenoxacin (T-3811 or BMS-284756)
Abstract
The palladium-catalyzed cross-coupling reaction of 5-(tributylstannyl)isoindoline and its 1- and 3-methyl derivatives with 6-fluoro or 6-unsubstituted 7-bromo-1-cyclopropyl-8-methoxy (or difluoromethoxy)-4-oxoquinoline-3-carboxylate afforded the corresponding 1-cyclopropyl-7-(5-isoindolinyl)-4-oxoquinoline-3- carboxylic acids: 6-fluoro, 1a-7a and 6-nonfluoro, 1b-7b. The in vitro antibacterial spectra of the newly synthesized quinolones were mostly characterized by excellent Gram-positive activity against Staphylococcus aureus and Streptococcus pneumoniae including quinolone-resistant strains, and also by significant Gram-negative activity comparable to 7-(1-piperazinyl)fluoroquinolones. Comparative examinations of the in vitro antibacterial profiles and the in vivo toxicity in terms of intravenous lethality, micronuclei-inducing potential and convulsive activity provided 6-nonfluorinated 1-cyclopropyl-8-(difluoromethoxy)-7-(1-methylisoindolin-5-yl)-4- oxoquinoline-3-carboxylic acid [(+/-)-5b] as the candidate for evaluation of the stereoisomers. The enantiomers (R)-5b and (S)-5b were synthesized via the Suzuki coupling reaction of (R)- and (S)-1-methyl derivatives of 2-(triphenylmethyl)isoindolin-5-boronic acid with the corresponding 7-bromo-8-(difluoromethoxy)-4- oxoquinoline-3-carboxylate. The (R)-5b stereoisomer proved to be 2- to 4-fold more active than the (S)-5b stereoisomer against the organisms tested, with the exception of an equal potency observed with S.…
How strong is the evidence?
Evidence Hub reads this as a experimental / empirical study, done in animal, not in people. Its evidence level is 5 of 5 (Very low · case / narrative / animal / in vitro / in silico). Case reports, narrative reviews, and animal, cell or computer-model studies give the weakest evidence for human health.
Read the paper
Related studies
- Severe clinical outcomes of COVID-19 associated with proton pump inhibitors: a nationwide cohort study with propensity score matching
- Levofloxacin-Induced Tendon Rupture: A Case Report and Review of the Literature
- Association between cord blood 25-hydroxyvitamin D concentrations and respiratory tract infections in the first 6 months of age in a Korean population: a birth cohort study (COCOA)
- Neuroprotective Effects of Epicatechin against Oxidative Stress-Induced Cognitive Impairment: A Systematic Review and Meta-Analysis
- Quality evaluation and in vitro interaction studies between levofloxacin 250mg and diclofenac sodium 50mg tablets
- Molecular Epidemiology of mcr-1 -Positive Polymyxin B-Resistant Escherichia coli Producing Extended-Spectrum β-Lactamase (ESBL) in a Tertiary Hospital in Shandong, China
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.