Tricyclic Fluoroquinolones Research Articles

Synthesis and antimycobacterial evaluation of new (2-oxo-2H-chromen-3-yl) substituted fluoroquinolones

An efficient method for incorporation of the cyanomethyl fragment into the benzene ring of bi- and tricyclic fluoroquinolones through the nucleophilic substitution of a fluorine atom with carbanions derived from CH-active cyanoacetates, followed by an acidic hydrolysis of the reaction intermediates was developed. The reaction of cyanomethyl derivatives of bi- and tricyclic fluoroquinolones with ortho-hydroxy substituted benzaldehydes proved to give the corresponding condensation products, which can be regarded as the key intermediates in the synthesis of previously unknown (2-oxo-2H-chromen-3-yl) substituted bi- and tricyclic fluoroquinolones. It has been shown that an increase in the reaction temperature and exposition time promotes the competitive process, leading to substitution of one more fluorine atom to give 1,4-dihydro[1]-benzoxepino[2,3-g]quinolones. New fluoroquinolones proved to exhibit anti-mycobacterial activity, thus indicating that a search of biologically active compounds in this family of heterocycles appears to be a reasonable approach.

Synthesis and antibacterial activity of novel [1,2,4]triazolo[3,4-h][1,8]naphthyridine-7-carboxylic acid derivatives

Abstract Novel tricyclic fluoroquinolones, [1,2,4]triazolo[3,4-h][1,8]naphthyridine-8-one-7-carboxylic acid derivatives 4a – 4h bearing carrying a functional Mannich-base moiety at the C-8 position, were synthesized and evaluated for their antimicrobial activity. The results showed that some compounds with a piperazine side chain exhibited comparable or better antibacterial activity than comparator cirprofloxacin. Furthermore, the targeted compounds also displayed a broad spectrum of activity against resistant strains including both Gram-negative and Gram-positive bacteria. In particular, compound 4h showed an MIC of 0.25 μg/mL in antibacterial assay against multiple drug-resistant Escherichia coli , which represents an about 30-fold increase of potency compared to ciprofloxacin. Thus, their excellent antibacterial activity against resistant strains suggests that triazole-fused fluoroquinolones warrant further optimization as novel anti-infective chemotherapies.

Antistaphylococcal Activity of WCK 771, a Tricyclic Fluoroquinolone, in Animal Infection Models

WCK 771, the arginine salt of S-(-)-nadifloxacin, was evaluated in animal models of staphylococcal infection and in vitro. For 302 methicillin-susceptible strains the MIC at which 50% of isolates are inhibited (MIC50) and the MIC90 of WCK 771 were 0.03 and 0.03 microg/ml, respectively, and for 198 methicillin-resistant strains the MIC50 and the MIC90 were 0.5 and 1.0 microg/ml, respectively. All methicillin-susceptible staphylococci were quinolone susceptible, and almost all methicillin-resistant staphylococci were quinolone resistant. WCK 771 was more potent than moxifloxacin, trovafloxacin, levofloxacin, and ciprofloxacin and had potency comparable to that of clinafloxacin. Only WCK 771 and clinafloxacin demonstrated strong potencies against vancomycin-intermediate Staphylococcus aureus strains (MICs = 1 microg/ml). WCK 771 is not a substrate of the NorA pump, as evident from the lack of an effect of reserpine on the MICs and similar protective doses against infections caused by efflux-positive and -negative staphylococci. WCK 771 was effective by both the oral and the subcutaneous routes in mice infected intraperitoneally with quinolone-susceptible methicillin-susceptible S. aureus (MSSA) strains. For infections caused by quinolone-resistant methicillin-resistant S. aureus (MRSA) strains, the activity of WCK 771 administered subcutaneously was superior to those of trovafloxacin and sparfloxacin, with a 50% effective dose range of 27.8 to 46.8 mg/kg of body weight. The activity of WCK 771 was superior to those of moxifloxacin, vancomycin, and linezolid in a mouse cellulitis model of infection caused by one MSSA and two MRSA strains, with effective doses of 2.5 and 5 mg/kg for the MSSA strain and 10-fold higher effective doses for MRSA strains. WCK 771, like vancomycin and linezolid, eradicated MRSA from mouse liver, spleen, kidney, and lung when it was administered subcutaneously at a dose of 50 mg/kg for four doses. These studies have demonstrated the effectiveness of WCK 771, administered orally and parenterally, for the treatment of diverse staphylococcal infections in mice, including those caused by quinolone-resistant strains.

Fused fluoroquinolones: synthesis and 1H and 19F NMR studies

New derivatives of fused fluoroquinolones bearing five aromatic rings have been obtained. The 19 F NMR spectra of these pentacyclic fluoroquinolones demonstrate unusual through space 1 H – 19 F and 19 F – 19 F spin–spin interactions with coupling constants 6J (F, H)=2.0–3.0 Hz, 7J (F, F)=3.5–4.0 Hz and 9J (F, H)=3.0–3.5 Hz. Relative reactivities of fluorine atoms in pentacyclic fluoroquinolones in the amino-defluorination reactions are also different relative to bi- and tricyclic fluoroquinolones.

Fluoro-containing Heterocycles: VI. New Derivatives of 1,3,4-Thiadiazino[6,5,4-i,j]quinoline

A series of new tricyclic fluoroquinolones was prepared by replacing fluorine atoms in derivatives of 2-R-8-Y-7-oxo-9,10-difluoro-7H-1,3,4-thiadiazino[6,5,4-i,j]quinoline-6-carboxylic acids. In acids and esters containing a hydrogen atom in position 8 occurred replacement of F10 by amine rests, and in compounds with a fluorine in position 8 was substituted either F8or F10 and F8depending on the amine character.

ChemInform Abstract: 1,3,4‐Oxa(thia)diazino[i,j]‐Anellated Quinolines: A New Type of Key Intermediate in the Synthesis of Tricyclic Fluoroquinolones.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

1,3,4-Oxa(thia)diazino [ i,j]-annelated quinolines: a new type of key intermediate in the synthesis of tricyclic fluoroquinolones

The synthesis of new derivatives of 1,3,4-oxa(thia)diazino[6,5,4- i,j ]quinolines, which have a structure that is very similar to the ofloxacin skeleton, by intramolecular cyclizations of ethyl 3-(R-carbonylhydrazino)- and 3-(R-thiocarbonylhydrazino)-substituted 2-polyfluorobenzoyl acrylates, is described.

Review of preclinical studies with ofloxacin.

Most Enterobacteriaceae, enteropathogens, and fastidious gram-negative bacteria are highly susceptible to ofloxacin, a new tricyclic fluoroquinolone. Aerobic gram-negative bacilli and gram-positive bacteria are generally not as susceptible to ofloxacin. Obligate anaerobes are generally resistant to ofloxacin, while many mycobacteria, chlamydiae, legionellae, and mycoplasmas are susceptible. Ofloxacin is generally less active than ciprofloxacin against gram-negative bacteria, is similarly active against gram-positive bacteria, mycobacteria, legionellae, and mycoplasmas, and is more active against chlamydiae. However, numerous animal studies have shown these two fluoroquinolones to be similar. Ofloxacin inhibits DNA synthesis, is rapidly bactericidal, and is 1,000-2,400 times more potent against prokaryotic gyrase than against eukaryotic gyrase. The bactericidal effect of ofloxacin is not completely neutralized by inhibitors of protein or RNA synthesis. Resistance to ofloxacin arises from mutations within chromosomal genes involved with DNA gyrase and drug permeation. Selection of resistant mutants by ofloxacin is not as frequent as that seen with nalidixic acid. However, due to the cross-resistance between ofloxacin and other fluoroquinolones, all of these drugs should be used judiciously to preserve their clinical utility.

Determination of rufloxacin, a new tricyclic fluoroquinolone in biological fluids using high-performance liquid chromatography with ultraviolet detection.

A simple, specific, and sensitive high-performance liquid chromatography method has been developed for routine monitoring of the antimicrobial agent rufloxacin in human serum and urine. Serum or urine-spiked with internal standard pipemidic acid, were vortex-mixed for 2 min with dichloromethane at pH 7.4. The evaporated extract was dissolved in 0.05 M NaOH. The mobile phase consisted of orthophosphoric acid, tetrabutylammonium iodide, and methanol. Drugs were resolved at ambient temperature on a 10 micron Viosfer LC-RP-18 column (250 x 4.6 mm I.D.) equipped with a guard column. Flow rate was 1.8 ml/min, and monitoring was performed at 295 nm. The calibration curve was linear from 0.1 to 10 micrograms/ml for human serum and from 0.05 to 10 micrograms/ml for urine. Retention times were 3.1 and 6.3 min for internal standard and rufloxacin. The detection limit of rufloxacin was 0.05 microgram/ml for human serum and 0.03 microgram/ml for urine. No interference from other commonly administered drugs or endogenous substances was observed. The assay demonstrated sufficient sensitivity and specificity for the study of the pharmacokinetics of rufloxacin in humans.

In vitro and in vivo antibacterial activities of E-4497, a new 3-amine-3-methyl-azetidinyl tricyclic fluoroquinolone

The in vitro and in vivo antibacterial activities of a new tricyclic fluoroquinolone, E-4497 [S(-)-9-fluoro-3-methyl-10-(3-amine-3-methyl-azetidin-1-yl)-7-oxo- 2,3-dihydro- 7H-pyrido-(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid], were evaluated in comparison with those of DR-3355 [S-(-)-ofloxacin], norfloxacin, and ciprofloxacin. E-4497 was more potent than norfloxacin and as potent as or more potent than DR-3355 and ciprofloxacin against Staphylococcus spp., Streptococcus spp., and Enterococcus faecalis. With the exception of Providencia spp., E-4497 inhibited 90% of the Enterobacteriaceae at less than or equal to 0.25 micrograms/ml. Against enteric bacteria, E-4497 was similar in potency to norfloxacin but less potent than DR-3355 and ciprofloxacin. For Pseudomonas aeruginosa, the MICs of E-4497, DR-3355, norfloxacin, and ciprofloxacin for 90% of strains were 2, 2, 4, and 0.5 micrograms/ml, respectively. Against Clostridium perfringens and Bacteroides fragilis, E-4497 (MICs for 90% of strains, 2 and 8 micrograms/ml, respectively) was two- to fourfold more active than norfloxacin and ciprofloxacin. E-4497 activity decreased moderately in the presence of 10 mM Mg2+. Urine at pH 5.5 caused a significant decrease in activity compared with urine at pH 7.2. However, the presence of serum either had no effect or increased the activity of E-4497. In general, E-4497 was bactericidal at the MIC. In systemic infections with Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli, and Pseudomonas aeruginosa in mice, the protective effect of E-4497 was generally greater than that of norfloxacin and comparable to those of DR-3355 and ciprofloxacin.