A series of novel 3-quinolinecarboxylic acid derivatives have been prepared and their antibacterial activity evaluated. These derivatives are characterized by fluorine attached to the 6-position and substituted amino groups appended to the 1- and 7-positions. Structure-activity relationship studies indicate that antibacterial potency is greatest when the 1-substituent is methylamino and the 7-substituent is either 4-methyl-1-piperazinyl, 16, or 1-piperazinyl, 21. Derivatives 16 and 21, the 1-methylamino analogues of pefloxacin and norfloxacin, respectively, show comparable in vitro and in vivo antibacterial potency to these two known agents. The activity (vs. Escherichia coli Vogel) of 16 (amifloxacin) is the following: in vitro MIC (microgram/mL) = 0.25; in vivo (mice) PD50 (mg/kg) = 1.0 (po), 0.6 (sc).

The antimicrobial activity of rosoxacin, a new quinoline antibacterial compound, was determined against the causative organisms of three sexually transmitted diseases. Rosoxacin demonstrated a high degree of activity against Neisseria gonorrhoeae clinical isolates, with the miniimal inhibitory concentrations for 50% of these being 0.03 ,ug/ml. The corresponding miniimal inhibitory concentrations for penicillin, ampicillin, tetracycline, and spectinomycin were 0.25 U/ ml, 0.125 ug/ml, 0.25 ,tg/ml, and 16 ,ug/ml, respectively. Eleven strains of Chlamydia trachomatis were inhibited by 5 ,ug of rosoxacin per ml, and each of seven Ureaplasma urealyticum strains was inhibited by 2 to 8 Ag of rosoxacin per ml. The results of these susceptibility studies, coupled with those of an earlier evaluation of the phannacokinetics of rosoxacin, provide support for extending or undertaking clinical evaluations of this compound against infections with N. gonorrhoeae, C. trachomatis, and U. urealyticum.Rosoxacin [1-ethyl-1,4-dihydro-4-oxo-7-(4-pyridinyl)-3-quinoline-carboxylic acid] (Fig. 1 Susceptibility tests were performed by an agar dilution method employing the foilowing medium: GC agar base (BBL) containing 1% hemoglobin (BBL) and 1% IsoVitaleX (BBL). Twofold serial concentrations of the antibacterial agents were incorporated into complete GC agar medium and poured into plastic petri dishes (100 by 15 mm; Fisher Scientific Co.). The cultures were grown on the surface of complete GC agar medium plates for 24 h at 37°C in a candle jar. Growth on the surface of each plate was washed off with Trypticase soy broth. Each suspeIsion was shaken with glass beads for 5 min on a paint shaker. The suspensions were adjusted spectrophotometrically with Trypticase soy broth to contain 10" colonyforming units per ml. The adjusted suspensions were further diluted in broth to contain 4 x 106 colonyforming units per ml. Samples (0.5 ml each) of the diluted cultures were added to the wells of a Steers replicator (8). Each point of the replicator delivered 0.0025 ml (104 colony-forming units per spot). All plates were inoculated with the replicator and incubated for 24 h at 370C in candle jars. The minimal inhibitory concentration (MIC) was read as the lowest concentration of antibacterial drug that completely inhibited growth.

WIN 49375 (amifloxacin) is a synthetic antibacterial agent of the quinolone class. It is similar in chemical structure to pefloxacin but differs by containing a methylamino, rather than an ethyl, substituent at the 1-N position. The activity of WIN 49375 in vitro was comparable to those of norfloxacin and pefloxacin against Enterobacteriaceae and generally greater than those of tobramycin and cefotaxime. WIN 49375 was more active in vitro than carbenicillin and mezlocillin against Pseudomonas aeruginosa isolates and showed moderate activity against Staphylococcus aureus, with MICs of <2 ,ug/ml. The in vitro activity of WIN 49375 was not markedly affected by the presence of human serum, the size of the bacterial inoculum, or changes in pH between 6 and 8. Against systemic, gram-negative bacterial infections in mice, WIN 49375 was generally less active than cefotaxime but more active than gentamicin. WIN 49548, the major piperazinyl-N-desmethyl metabolite of WIN 49375, was as effective as the parent drug against experimental infections in mice when given parenterally. When administered orally, however, this metabolite was less potent than WIN 49375. WIN 49375 was highly active by the oral route, with 50% effective doses within two-to threefold of those obtained with parenteral medication.

The antibacterial activity of a new 7-dimethylpyridinyl quinolone, WIN 57273, was assessed by using in vitro and in vivo models. Agar inclusion and broth dilution in vitro tests revealed broad-spectrum activity against gram-positive and selected gram-negative organisms, with the greatest potency observed against the staphylococci. The MIC for 90% of coagulase-positive strains tested (MIC90) was <0.002 ,ug/ml; for the coagulasenegative strains the MIC90 was 0.008 ,ug/ml. Against enterococci the MIC90 was 0.06 ,ug/ml, with comparable activity observed against group A and group B streptococci as well as against the pneumococci. In general, the MIC90s for the gram-negative bacteria were <1 ,ug/ml. Exceptions were Serratia marcescens (MIC90, 16 ,ug/ml), Citrobacterfreundii (MICgo,4 ,ug/ml), and Pseudomonas aeruginosa (MIC90, 8 jg/ml). The greatest potency was observed against Haemophilus spp. and Neisseria spp., with MIC90s of 0.06 and 0.016 ,ug/ml, respectively. Broad-spectrum activity was also observed against anaerobes, with MIC90s ranging from 0.125 to 0.5 ,ug/ml among the species tested. The in vivo efficacy was determined by using a murine model by calculating the 50% protective doses against a lethal bacterial infection caused by strains of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The staphylococci were most susceptible, with 50% protective doses for all strains ranging from 0.1 to 0.7 mg/kg. With the exception of the Pseudomonas infection, which was refractory to treatment, animals that were part of the other infection models responded to less than 10 mg/kg. Equivalent activity was seen with the subcutaneous or the oral route of drug administration. WIN 57273 was significantly more potent than ciprofloxacin in treating gram-positive bacterial infections (2-to 20-fold) but was significantly less effective at treating gram-negative bacterial infections (30-to 300-fold).During the past several years a renewed focus of laboratory and clinical research activities has been placed on quinolone antibacterial agents. Numerous new compounds have been described in the literature, with several new agents reaching general clinical use. While the most extensively studied and most successful candidate has been ciprofloxacin, the search has continued for further improvements in potency and pharmacokinetic profile. To complement the spectrum of activity exhibited by ciprofloxacin, with its excellent potency against gram-negative bacteria, a recent focus has been on compounds with improved activities against gram-positive bacteria and anaerobes. This is exemplified by compounds such as CI-934 (3, 9), A-60969 (T-3262) (1, 2), PD 117,596 (8), and PD 127,391 (6, 10).Research efforts in our laboratories have centered on a study of the effects of a dimethylpyridinyl substitution at the 7 position of the quinolone ring. Previous studies have shown this modification to impart pote...

The syntheses of 1-(arylamino)-1H-pyrroles and 4-(1H-pyrrol-1-ylimino)-2-5-cyclohexadienes are described. Several of these compounds express in vitro antibacterial activity or can be metabolized to show in vitro antibacterial activity, and a few examples have shown efficacy against tuberculosis in mice. One compound, N,N'-(2,5-cyclohexadiene-1,4-diylidene)bis-1H-pyrrol-1-amine, is completely effective at 6.25 mg/kg against Mycobacterium tuberculosis H37Rv.