To discover novel antitumor rhodanine unsaturated ketones, a series of fluoroquinolone (rhodanine α, β-unsaturated ketone) amine derivatives (5a-5r) were designed and synthesized with fluoroquinolone amide scaffold as a carrier. The structures of eighteen title compounds were characterized by elemental analysis, 1H NMR and MS. The in vitro anti-proliferative activity against Hep-3B, Capan-1 and HL60 cells was evaluated by MTT assay. The results showed that the title compounds not only had more significant anti-proliferative activity against three tested cancer cell lines than that of the parent ciprofloxacin 1, but also exhibited the highest activity against Capan-1 cells. The SAR revealed that some compounds carrying aromatic heterocyclic rings or phenyl attached to an electron-withdrawing carboxyl or sulfonamide substituent were comparable to or better than comparison doxorubicin against Capan-1 cells. As such, it suggests that fluoroquinolone (rhodanine α, β-unsaturated ketone) amines are promising leads for the development of novel antitumor fluoroquinolones or rhodanine analogues.
Amides ; chemical synthesis ; pharmacology ; Antineoplastic Agents ; chemical synthesis ; pharmacology ; Cell Line, Tumor ; Fluoroquinolones ; chemical synthesis ; pharmacology ; HL-60 Cells ; Humans ; Ketones ; chemical synthesis ; pharmacology ; Rhodanine ; chemical synthesis ; pharmacology

OBJECTIVETo evaluate the role of outer membrane protein (Omp) F-deficiency and active efflux in the accumulation of hydrophilic fluoroquinolones ciprofloxacin (CPLX) and lomefloxacin (LMLX) in resistant E. coli strains.

METHODSFluoroquinolone accumulation in bacteria and the effect of active efflux were measured by a fluorescence method. The outer membrane proteins of the bacteria were analysed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). E. coli strains in this study included control strains JF701 and JF703 that are OmpC- or OmpF-deficient mutants of E. coli K-12, respectively, and the fluoroquinolone susceptible strain the fluoroquinolone susceptible strain of Escherichia coli (Ecs) and its in vitroselected resistant strains R2 and R256, and the clinical resistant isolates R5 and R6.

RESULTSThe steady-state accumulation concentration of each drug in Ecs appeared to be the same as in JF701, while in the OmpF-deficient strain JF703, it was 1/5 CPLX or 1/2 LMLX lower than that in JF701, but JF703 was still susceptible to fluoroquinolones. On the other hand, compared with susceptible strains, a 2- to 10-fold decrease in the accumulation of each drug was found in the resistant strains except R2, in which the accumulation was slightly higher than in JF703. After the addition of 2,4-dinitrophenol (DNP), accumulation of each drug increased, especially in resistant strains, indicating that the function of the active efflux (pump) system in these bacteria had been enhanced dramatically. Furthermore, both OmpF and OmpC in Ecs, OmpF-deficiency in R2 and R256 and OmpC-deficiency in R5 and R6 were observed.

CONCLUSIONThe decreased accumulation of hydrophilic fluoroquinolones in E. coli involved OmpF-deficiency and active efflux (pump), and the latter may be an important factor.

2,4-Dinitrophenol ; pharmacology ; Anti-Infective Agents ; metabolism ; pharmacology ; Ciprofloxacin ; metabolism ; pharmacology ; Drug Resistance, Bacterial ; Escherichia coli ; drug effects ; metabolism ; Fluoroquinolones ; Porins ; physiology ; Quinolones ; metabolism ; pharmacology

To discover novel antitumor fluoroquinolone lead compounds from a rational modification for antibacterial fluoroquinolones, a fused heterocyclic ketone corresponding to thiazolo[2,3- b][1,2,4]triazolone used as a bioisosteric replacement of the C-3 carboxylic acid group of ciprofloxacin 1, and further modification by a Claisen condensation reaction with substituted benzaldehydes formed novel fluoroquinolone C-3 fuse heterocyclic α, β-unsaturated ketones as the title compounds (6a-6r), separately. The structures of eighteen title compounds were characterized by elemental analysis, 1H NMR and MS, and the in vitro anti-proliferative activity against human hepatoma Hep-3B cells, pancreatic Capan-1 cells and leukemia HL60 cells was evaluated by a MTT assay. The preliminary results showed that the title compounds not only had more significant anti-proliferative activity against three tested cancer cell lines than that of the parent ciprofloxacin 1, but also exhibited the highest activity against Capan-1 cells. In particular, compounds carrying an electron-withdrawing carboxyl (6k, 6m) or sulfonamide substituent (6q, 6r) attached to benzene ring were comparable to or better than constractive drug doxorubicin against Capan-1 cells. As such, it suggests that it is favorable for a fused heterocyclic α, β-unsaturated ketone scaffold instead of the C-3 carboxylic acid group to improve the antitumor activity of fluoroquinolones.
Anti-Bacterial Agents ; Antineoplastic Agents ; chemical synthesis ; pharmacology ; Cell Line, Tumor ; Ciprofloxacin ; analogs & derivatives ; Fluoroquinolones ; chemical synthesis ; pharmacology ; HL-60 Cells ; Humans ; Ketones ; pharmacology ; Structure-Activity Relationship

BACKGROUND: Antimicrobial susceptibility of Legionella spp. has rarely been studied in Korea. Therefore, we aimed to determine the susceptibility of Legionella spp. to various antibiotics. METHODS: We assessed the antimicrobial susceptibility of 66 environmental and clinical Legionella isolates collected between January 2001 and December 2008 from Korea and Japan. The minimum inhibitory concentrations (MICs) of 6 antibiotics, namely, azithromycin, ciprofloxacin, clarithromycin, clindamycin, gatifloxacin, and gemifloxacin were determined by the broth microdilution method using buffered starch yeast extract broth. RESULTS: The MIC ranges of the 6 antibiotics used against the Legionella isolates were as follows: 0.004-0.062 microgram/mL (azithromycin), 0.002-0.5 microgram/mL (ciprofloxacin), 0.004-0.5 microgram/mL (clarithromycin), 0.12-4 microgram/mL (clindamycin), 0.002-0.12 microgram/mL (gatifloxacin), and 0.008-1 microgram/mL (gemifloxacin). CONCLUSIONS: Legionella spp. isolates from Korea and Japan were most susceptible to gatifloxacin. Azithromycin, clarithromycin, ciprofloxacin, and gemifloxacin were also effective for treating legionellosis.
Anti-Bacterial Agents/*pharmacology ; Azithromycin/pharmacology ; Ciprofloxacin/pharmacology ; Clarithromycin/pharmacology ; Clindamycin/pharmacology ; Drug Resistance, Bacterial ; Fluoroquinolones/pharmacology ; Humans ; Legionella/*drug effects/isolation & purification ; Legionellosis/diagnosis/microbiology ; Microbial Sensitivity Tests ; Naphthyridines/pharmacology

Gatifloxacin (GFX) is a kind of chiral fluoroquinolones compound due to the methyl group at the C-3 position of the piperazine ring[1]. Although the enantiomers of GFX show similar levels of antimicrobial activity and pharmacokinetics[2], the other biological activities (i.e., toxicity or enantioselective recognition to various receptors in vivo) of GFX enantiomers have not yet been studied. With this in mind, we developed a rapid and cost-effective high performance liquid chromatographic (HPLC) separation procedure for GFX enantiomers with a pre-column esterification strategy. With significant enhancement of drug solubility and optimization for chromatographic conditions, the proposed method was scaled up to preparative HPLC to obtain optical active S-(-)- and R-(+)-GFX. The antibacterial activities of GFX enantiomers after preparative separation were further verified by measuring the Minimum Inhibitory Concentration (MIC) values against Escherichia coli ATCC 25922. In addition, the binding selectivity of GFX enantiomers to protein receptor were evaluated by antibody using enzyme-linked immunosorbent assay (ELISA) for the first time.
Anti-Bacterial Agents ; chemistry ; pharmacology ; Escherichia coli ; drug effects ; Esterification ; Fluoroquinolones ; chemistry ; pharmacology ; Microbial Sensitivity Tests ; Molecular Structure ; Structure-Activity Relationship

Antimicrobial susceptibility testing was conducted with 6 different spirochetal strains (4 strains of Leptospira spp. and 2 strains of Borrelia burgdorferi) against 3 antimicrobial agents, commonly used in equine and bovine practice. The ranges of MIC and MBC of amoxicillin against Leptospira spp. were 0.05 - 6.25 microgram/ml and 6.25 - 25.0 microgram/ml, respectively. And the ranges of minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of amoxicillin against B. burgdorferi were 0.05 - 0.39 microgram/ml and 0.20 - 0.78 microgram/ml, respectively. The ranges of MIC and MBC of enrofloxacin against Leptospira spp. were 0.05 - 0.39 microgram/ml and 0.05 - 0.39 microgram/ml, respectively. Two strains of B. burgdorferi were resistant to enrofloxacin at the highest concentration tested for MBC (> or = 100 microgram/ml). Therefore, the potential role of tilmicosin in the treatment of leptospirosis and borreliosis should be further evaluated in animal models to understand whether the in vivo studies will confirm in vitro results. All spirochetal isolates were inhibited (MIC) and were killed (MBC) by tilmicosin at concentrations below the limit of testing (< or = 0.01 microgram/ml).
Amoxicillin/pharmacology ; Anti-Bacterial Agents/*pharmacology ; Borrelia burgdorferi/*drug effects/growth & development/isolation & purification ; Fluoroquinolones/pharmacology ; Leptospira/*drug effects/growth & development/isolation & purification ; Leptospirosis/*microbiology ; Lyme Disease/*microbiology ; Macrolides/pharmacology ; Microbial Sensitivity Tests ; Reproducibility of Results ; Tylosin/analogs & derivatives/pharmacology

OBJECTIVETo study the phenotypic and genotypic resistance to Fluoroquinolones in Neisseria gonorrhoeae (NG) isolated in Jiangsu province of China.

METHODSIn-vitro, susceptibility testing of ciprofloxacin and levofloxacin against ninety-five clinical isolates were determined by agar dilution method. Detection of mutation in the gyrA and parC genes was performed by polymerase chain reaction (PCR) assay and sequence analysis.

RESULTSThe clinical isolates demonstrated 100% resistance to ciprofloxacin. Based on gyrA and parC mutations, 18 types could be categorized among the 54 isolates. Based on the same gyrA mutations,isolates with high MIC appeared to have had more mutations in parC gene.

CONCLUSIONThe status of resistance to ciprofloxacin in NG was quite serious, and ciprofloxacin treatment for the treatment of NG infections in Jiangsu province should not be recommended. The results from this study suggested that mutations in the parC gene had contributed to the development of high Fluoroquinolone resistance in NG.

China ; DNA Gyrase ; genetics ; DNA Topoisomerase IV ; genetics ; Drug Resistance, Bacterial ; Fluoroquinolones ; pharmacology ; Genotype ; Gonorrhea ; drug therapy ; Humans ; Neisseria gonorrhoeae ; drug effects ; genetics ; isolation & purification ; Phenotype

Humans ; Mycobacterium tuberculosis/genetics* ; Microspheres ; Antitubercular Agents/pharmacology* ; Mutation ; Microbial Sensitivity Tests ; Fluoroquinolones ; Drug Resistance, Bacterial/genetics* ; Tuberculosis, Multidrug-Resistant/microbiology*

AIMTo synthesize new fluoroquinolone analogues as antibacterial compounds.

METHODS AND RESULTSBy reaction of acryl chloride(chloro-carbonic ester) with sodium sulfocyanate, acyl isosulfocyanic ester were easily obtained. Twelve 7-(4-acylamino-thiocarbamoyl-1-piperazinyl) fluoroquinolone analogues (1-12) were synthesized through modifying the 7-piperazine of norflorxacin and ciprofloxacin with isosulfocyanic ester synthesized above. The structures of synthesized compounds were characterized by 1HNMR, IR and elemental analysis.

CONCLUSIONAntibacterial activities of the new compounds were evaluated in vitro compared with norflorxacin. Compounds 5, 7, 10 and 12 showed antibacterial activities.

Anti-Infective Agents ; chemical synthesis ; chemistry ; pharmacology ; Bacillus subtilis ; drug effects ; Ciprofloxacin ; chemistry ; pharmacology ; Combinatorial Chemistry Techniques ; methods ; Escherichia coli ; drug effects ; Fluoroquinolones ; chemical synthesis ; chemistry ; pharmacology ; Microbial Sensitivity Tests ; Molecular Structure ; Norfloxacin ; chemistry ; pharmacology

PURPOSE: Fluoroquinolones, rapidly gaining prominence in treatment of Stenotrophomonas maltophilia (SMP), are noted for their potency and tolerability. However, SMP may rapidly acquire resistance to fluoroquinolones. We evaluated associations of clinical factors with acquisition of levofloxacin resistance (LFr) in SMP. MATERIALS AND METHODS: Our retrospective cohort study was based on patient data collected between January 2008 and June 2010. Through screening of 1275 patients, we identified 122 patients with data for SMP antibiotic susceptibility testing in > or =3 serial SMP isolates. RESULTS: We assigned the 122 patients to either the SS group (n=54) in which levofloxacin susceptibility was maintained or the SR group (n=31) in which susceptible SMP acquired resistance. In multivariate regression analysis, exposure to levofloxacin for more than 3 weeks [odds ratio (OR) 15.39, 95% confidential interval (CI) 3.08-76.93, p=0.001] and co-infection or co-colonization with Klebsiella pneumoniae resistant to levofloxacin (OR 4.85, 95% CI 1.16-20.24, p=0.030) were independently associated with LFr acquisition in SMP. CONCLUSION: Acquisition of LFr during serial sampling of SMP was related to the levofloxacin exposure.
Aged ; Anti-Bacterial Agents/*pharmacology/*therapeutic use ; Fluoroquinolones/pharmacology/therapeutic use ; Gram-Negative Bacterial Infections/drug therapy ; Humans ; Levofloxacin/*pharmacology/*therapeutic use ; Microbial Sensitivity Tests ; Middle Aged ; Retrospective Studies ; Stenotrophomonas maltophilia/drug effects/*pathogenicity