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)

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 difluorometh-oxy)-4-oxoquinoline-3-carboxylate afforded the corresponding 1 -cyclopropyl-7-(5-isoindolinyl)-4-oxoquinoline-3-carboxylic acids: 6-fluoro, la-7a and 6-nonfluoro, lb-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-resist-ant 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-nonfluorin-ated 1 -cyclopropyl-8-(difluoromethoxy) -7-(1-methylisoindolin-5-yl)-4-oxoquinol-ine-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-oxoquinoli-ne-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. pneumoniae IID553 and Haemophilus influenzae ATCC49247. A noticeable in vitro antibacterial profile of (R) -5b was that it is 16- and 64-fold more active than levoflox-acin (CAS 100986-85-4) and ciprofloxacin (CAS 86393-32-0), respectively, against Mycoplasma pneumoniae IID813 (MIC of 0.0313 µ g/ml), and 4-fold more active than ciprofloxacin and levofloxacin against Mycobacterium tuberculosis M-4 (MIC of 0.0313 µ g/ml). Additional studies indicate that (R)-5b (T-3811, CAS 194804-75-6) exhibits excellent antibacterial activity against a wide range of organisms including anaerobes and common respiratory pathogens, while demonstrating a high selectivity against the mammalian homolog topoisomerases. The methane-sulfonate of (R)-5b (T-3811ME, CAS 223652-90-2) is now undergoing clinical testings.