Synthesis of novel 5-fluoro analogues of norfloxacin and ciprofloxacin.

A series of polyfluoro-3-quinolonecarboxylic acids have been synthesized and their in vitro antibacterial activity evaluated. The desired 7-(substituted amino) derivatives were prepared from the 5,6,7,8-tetrafluoroquinolone acids. Conversely, amine displacement occurred primarily at the 5-position when the ester was used. Structure-activity studies indicated that the antibacterial activity was greatest when the N-1 substituent was cyclopropyl and the 7-substituent was 4-methyl-1-piperazinyl. All 5-(substituted amino) derivatives showed poor in vitro activity.

Pyrido[3,4-e]-1,2,4-triazines and related heterocycles as potential antifungal agents.

The preparation and biological activities of a series of pyrido[3,4-e]-1,2,4-triazines, 1,2,4-triazino[5,6-c]quinolines, and related fused triazines are described. Methyl, amino, and acylamino substituents were placed in the pyridyl ring of the former system. Other structural modifications included various alkyl, cycloalkyl, substituted phenyl, and heterocyclic groups in the 3-position of these ring systems. In agar dilution assays, actives in this series inhibited strains of Candida, Aspergillus, Mucor, and Trychophyton species at MIC's of less than or equal to 16 micrograms/mL.

Synthesis and structure-activity relationships of new 7-[3-(fluoromethyl)piperazinyl]- and -(fluorohomopiperazinyl)quinolone antibacterials.

Some novel 6-fluoro-7-substituted-1,4-dihydro-4-oxoquinoline-3-carboxylic acids have been prepared. At the N-1 position "standard" substitution was employed with the ethyl, cyclopropyl, and p-fluorophenyl groups being used. At C-7 the introduction of some novel piperazines was made. Most notably, 2-(fluoromethyl)piperazine (10) and hexahydro-6-fluoro-1H-1,4-diazepine (16, fluorohomopiperazine) at the quinolone C-7 position produced products with similar in vitro antibacterial activity as the ciprofloxacin reference. The in vivo efficacy of 1-cyclopropyl-6-fluoro-7-[3-(fluoromethyl)piperazinyl]-1,4-dihydro-4- oxoquinoline-3-carboxylic acid (20) was excellent with better oral absorption than ciprofloxacin (2).

In vitro activity of piperacillin/tazobactam against isolates from patients enrolled in clinical trials.

The in vitro activity of piperacillin alone or titrated with a constant concentration of 4 mug/ml tazobactam was evaluated against 3962 baseline pathogens isolated from 1899 patients enrolled in 9 clinical trial studies in North America. Tazobactam increased susceptibility rates of piperacillin for Enterobacteriaceae from 81% to 96%, Staphylococcus (methicillin susceptible) spp. from 6% to 100%, Bacteroides fragilis group from 79% to >99% and Haemophilus from 85% to 98%. The excellent activity of piperacillin against Pseudomonas, Streptococcus and Enterococcus was maintained in the presence of tazobactam. Overall piperacillin/tazobactam had better activity than ticarcillin/clavulanic acid, ceftazidime, and in general equaled the activity of imipenem. The excellent in vitro, extended-spectrum activity of piperacillin/tazobactam suggests its utility for various infections.

Synthesis and in vitro antibacterial activity of some 1-(difluoromethoxyphenyl)quinolone-3-carboxylic acids.

We report on the synthesis of N-1-phenylquinolones in which the difluoromethoxy moiety is utilized as a halogen replacement. The antibacterial activity is discussed with reference to N-1-halophenylquinolones.

Glycocinnamoylspermidines, a new class of antibiotics. V. Antibacterial evaluation of the isopropyl derivative of LL-BM123gamma.

Isopropyl LL-BM123gamma, a novel semisynthetic glycocinnamoylspermidine antibiotic, was active in vitro against both Gram-negative and Gram-positive bacteria with broad spectrum bactericidal activity against clinically important Gram-negative strains. In parallel tests, it was equal to or more potent than reference aminoglycoside antibiotics against Escherichia coli, Proteus, Enterobacter-Klebsiella, Serratia, Salmonella, and Acinetobacter strains. Against clinical isolates of Pseudomonas aeruginosa, isopropyl LL-BM123gamma compared favorably with gentamicin, verdamicin and amikacin but was less potent than tobramycin. Isopropyl LL-BM123gamma was active against many Gram-negative bacteria that were relatively resistant to aminoglycosides. It was rapidly absorbed following subcutaneous administration in mice and showed greater potency than gentamicin on both dosage and plasma concentration bases against several experimental infections.

New antitumor antibiotic, LL-D05139 beta. Fermentation, isolation, structure determination and biological activities.

The LL-D05139 complex, containing LL-D05139 beta and azaserine, was recovered from the fermentation filtrate of Glycomyces harbinensis (NRRL 15337). A chemically defined medium was developed which favored the production of LL-D05139 beta. Antibiotic LL-D05139 beta was isolated from the fermentation filtrate by adsorption on granular carbon and further purified by chromatography on microcrystalline cellulose. Acid hydrolysis of LL-D05139 beta gave one molar equivalent each of alanine and serine. Both amino acids were found to have the L-configuration by GC analysis on a chiral column and alanine was assigned to be the N-terminal amino acid by Edman degradation. This information coupled with IR, UV, 1H NMR, 13C NMR and MS spectral data allowed us to assign the structure of LL-D05139 beta as alanylazaserine. LL-D05139 beta demonstrated greater antibacterial and biochemical induction assay activities than azaserine. The two drugs showed similar antitumor activities.

LL-E19085 alpha, a novel antibiotic from Micromonospora citrea: taxonomy, fermentation and biological activity.

A new antibacterial antibiotic, designated LL-E19085 alpha, was isolated from the fermentation broth of an actinomycete strain. Based on cultural, physiological, morphological and chemical characteristics, culture LL-E19085 was identified as a new subspecies of Micromonospora citrea. Antibiotic LL-E19085 alpha demonstrated potent activity against a spectrum of Gram-positive aerobic and anaerobic bacteria.

Components and degradation compounds of the avoparcin complex.

The isolation and characterization of many of the components of the avoparcin complex are described. A number of mild degradations products from this complex are similarly treated. Conditions for the analytical and preparative HPLC resolution of these materials are outlined.

Glycocinnamoylspermidines, a new class of antibiotics. II. Isolation, physiocochemical and biological properties of LL-BM123beta, gamma1 and gamma2.

LL-BM123beta, gamma1 and gamma2 are three new antibiotics produced by fermentation of an unidentified species of Nocardia. These strongly basic, water soluble compounds were isolated from the culture filtrate by CM-Sephadex ion-exchange and carbon chromatography. All three antibiotics are active against both gram-positive and gram-negative bacteria. A mixture of LL-BM123 gamma1 and gamma2 is more active than the beta component but generally less active than gentamicin.

LL-D49194 antibiotics, a novel family of antitumor agents: taxonomy, fermentation and biological properties.

A novel family of antitumor antibiotics, designated LL-D49194, was isolated from the fermentation broth of an actinomycete strain identified as Streptomyces vinaceus-drappus. LL-D49194 alpha 1 and beta 2 were active against Gram-positive and inactive against Gram-negative bacteria in vitro. The beta 1 component was not active against either Gram-positive or Gram-negative bacteria. These antibiotics exhibited significant in vivo activities against several murine tumors, albeit with differing potencies.

LL-E19020 alpha and beta, animal growth promoting antibiotics: taxonomy, fermentation and biological activity.

Antibacterial antibiotics LL-E19020 alpha and beta were isolated from the fermentation broth of an actinomycete strain. Based on cultural and physiological characteristics, culture LL-E19020 was identified as a new subspecies of Streptomyces lydicus. The LL-E19020 alpha and beta antibiotics were found to possess a very narrow antibacterial spectrum against human pathogens. In studies in chickens, LL-E19020 alpha demonstrated excellent growth promoting activity.

Calicheamicins, a novel family of antitumor antibiotics. 3. Isolation, purification and characterization of calicheamicins beta 1Br, gamma 1Br, alpha 2I, alpha 3I, beta 1I, gamma 1I and delta 1I.

Novel antitumor antibiotics, calicheamicins beta 1Br, gamma 1Br, alpha 2I, alpha 3I, beta 1I, gamma 1I and delta 1I were recovered from the fermentation broth of Micromonospora echinospora ssp. calichensis by solvent extraction, selective precipitation, normal phase, reversed phase and partition chromatography. The individual components were characterized by their UV, IR, 1H and 13C NMR spectral data.

Calicheamicins, a novel family of antitumor antibiotics: taxonomy, fermentation and biological properties.

A novel family of antitumor antibiotics, the calicheamicins, were isolated from the fermentation broth of Micromonospora echinospora subsp. calichensis. These antibiotics exhibited significant activity against Gram-positive and Gram-negative bacteria in vitro. Calicheamicin gamma 1I demonstrated antitumor activity against P388 leukemia and B16 melanoma in vivo.

In vitro and in vivo efficacy of YTR-830H and piperacillin combinations versus beta-lactamase-producing bacteria.

YTR-830H, a beta-lactamase inhibitor, is a non-amino penicillanic sulfone. In vitro synergistic activity with piperacillin was determined for 226 beta-lactamase producing clinical cultures. Combination of piperacillin: YTR in ratios of 2:1, 4:1, and 8:1 were highly effective vs Escherichia coli, Proteus, Providencia, Morganella, Staphylococcus, and Bacteroides. Minimum inhibitory concentrations (MICs) of piperacillin were reduced from the resistant to susceptible range. The higher ratios were less effective vs Enterobacter, Serratia, and Citrobacter. YTR-830H was not antagonistic with piperacillin. Combinations of 2:1, 4:1, and 8:1 increased the therapeutic effectiveness of piperacillin 8 - to 36 - fold against acute lethal infections produced in mice with piperacillin-resistant Escherichia coli, Klebsiella pneumoniae, Morganella morganii, and Staphylococcus aureus.