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Tosufloxacin tosylate hydrate, formerly known as T-3262 and A-61827, is a potent fluoroquinolone antibiotic used to treat susceptible infections. It has a controversial safety profile in relation to other fluoroquinolones. It is associated with severe thrombocytopenia and nephritis, and hepatotoxicity. It is sold in Japan under the brand name Ozex.
| Targets |
Quinolone
DNA gyrase (The 50% inhibitory dose (ID50) for supercoiling activity of E. coli DNA gyrase is 0.20 μg/mL). [1] |
|---|---|
| ln Vitro |
Antibacterial activities against S. aureus, Staphylococcus epidermidis, streptococci, enterococci, Bacteroides fragilis, Clostridium difficile, and Clostridium perfringens have been demonstrated by tosufloxacin tosylate hydrate (T-3262) (0.05-3.13 μg/mL; 18 h)[2].
Tosufloxacin tosylate hydrate (T-3262, A61827) exhibited a broad spectrum of antibacterial activity against gram-positive and gram-negative bacteria. The MIC90 values against clinical isolates were as follows: Staphylococcus aureus: 0.05 μg/mL; Staphylococcus epidermidis: 0.05 μg/mL; Streptococcus pyogenes: 0.39 μg/mL; Streptococcus pneumoniae: 0.10 μg/mL; Enterococcus faecalis: 0.39 μg/mL; Enterococcus faecium: 1.56 μg/mL. For Enterobacteriaceae such as Escherichia coli, MIC90 was 0.05 μg/mL, comparable to ciprofloxacin. Against Pseudomonas aeruginosa, MIC90 was 0.39 μg/mL, equal to ciprofloxacin. It was also active against Haemophilus influenzae (MIC90 0.0125 μg/mL), Neisseria gonorrhoeae (MIC90 0.0125 μg/mL), and obligate anaerobes like Bacteroides fragilis (MIC90 1.56 μg/mL). Against methicillin-resistant S. aureus, its MIC90 (0.20 μg/mL) was eightfold lower than ofloxacin. It maintained activity against nalidixic acid-resistant and gentamicin-resistant gram-negative bacteria. [1] Tosufloxacin tosylate hydrate (T-3262, A61827) showed bactericidal activity against S. aureus Smith, E. coli ML4707, and P. aeruginosa GN11189 at concentrations near its MIC, reducing viable cells to less than 1% within 2-4 hours, though regrowth was observed for S. aureus and P. aeruginosa at the MIC after 24 hours. [1] The frequency of spontaneous mutants resistant to Tosufloxacin tosylate hydrate (T-3262, A61827) was low. For S. aureus Smith, frequency was 1.3 x 10^-7 at 2x MIC and <7.7 x 10^-9 at 4x MIC. For E. coli ML4707, frequency was <1.1 x 10^-9 at 2x MIC. For P. aeruginosa GN11189, frequency was 3.8 x 10^-9 at 2x MIC and <1.3 x 10^-9 at 4x MIC. [1] |
| ln Vivo |
The antibacterial activity of tosufloxacin tosylate hydrate (T-3262) (oral gavage; 0.16–13.39 mg/kg; once) against S. aureus, E. coli, and P. aeruginosa has been demonstrated in vivo[2].
In a murine systemic infection model, the oral ED50 of Tosufloxacin tosylate hydrate (T-3262, A61827) against S. aureus Smith infection was 1.65 mg/kg, which was about 6 times lower than that of ofloxacin and about 20 times lower than that of norfloxacin. [1] Against systemic infection caused by E. coli ML4707, the oral ED50 was 0.22 mg/kg, comparable to ciprofloxacin (0.33 mg/kg). [1] Against systemic infection caused by P. aeruginosa GN11189, the oral ED50 was 10.13 mg/kg, superior to ofloxacin (24.04 mg/kg) and norfloxacin (70.71 mg/kg), and comparable to ciprofloxacin (9.48 mg/kg). [1] |
| Enzyme Assay |
The inhibitory effect on E. coli DNA gyrase supercoiling activity was assessed. Crude enzyme was prepared from E. coli K-12 strain KL-16 by lysozyme treatment and ammonium sulfate fractionation. The enzyme was further purified using a novobiocin-Sepharose column. The reaction mixture contained subunit A and B proteins, the drug solution, and pBR322 DNA relaxed by topoisomerase I. The mixture was incubated at 37°C for 2 hours. The reaction was stopped by adding proteinase K to a final concentration of 1%. The DNA products were analyzed by 0.8% agarose gel electrophoresis at 15 V/cm. The gel was stained with ethidium bromide and photographed under UV light. The 50% inhibitory dose (ID50) was defined as the drug concentration that reduced supercoiling activity by half, determined by densitometric tracing of the gel negatives. [1]
|
| Cell Assay |
Cell Line: Staphylococcus epidermidis, S. aureus, Bacteroides fragilis, Clostridium difficile, and Clostridium perfringens are among the bacteria that can cause food poisoning.
Concentration: 0.05-3.13 μg/mL Incubation Time: 18 hours Result: Showed MIC90s (MICs for 90% of the isolates tested) ranging from 0.05 to 1.56 μg/mL for S. aureus, Staphylococcus epidermidis, streptococci, and enterococci. Showed MIC90s of 1.56, 3.13, and 0.20 μg/mL for Bacteroides fragilis, Clostridium difficile, and Clostridium perfringens, respectively. |
| Animal Protocol |
Animal Model: Male Slc:ICR mice infected with S. aureus[2]
Dosage: 1.27-2.15 mg/kg Administration: Oral gavage; 1.27-2.15 mg/kg; once Result: demonstrated a 1.62 mg/kg (body weight) 50% effective dose (ED50) seven days post-infection. revealed a MIC of 0.0125 μg/mL. The in vivo antibacterial activity was evaluated in a murine systemic infection model. Male ICR mice (19-21 g) were used. Overnight cultures of test strains (S. aureus Smith, E. coli ML4707, P. aeruginosa GN11189) in brain heart infusion broth were suspended in 5% gastric mucin (for S. aureus and P. aeruginosa) or saline (for E. coli). A 0.2 mL bacterial suspension, containing a challenge dose approximately 10 times the minimal lethal dose, was administered intraperitoneally to each mouse. Drugs, including Tosufloxacin tosylate hydrate (T-3262, A61827), were suspended in 0.2% methyl cellulose and administered orally immediately after infection. Survival rates were monitored for 7 days post-infection, and the 50% effective dose (ED50) was calculated using the probit method. [1] |
| References | |
| Additional Infomation |
Toshufloxacin tosylate hydrate is a racemic mixture composed of equimolar amounts of (R)- and (S)-toshufloxacin tosylate hydrates. It possesses antibacterial, anti-infective, DNA synthesis inhibitory, hepatotoxic, and topoisomerase IV inhibitory effects. It comprises (S)-toshufloxacin tosylate hydrate, (R)-toshufloxacin tosylate hydrate, and toshufloxacin tosylate.
Toshufloxacin tosylate hydrate (T-3262, A61827) is a novel fluoroquinolone antibacterial agent, chemically named p-tosylate of DL-7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthidine-3-carboxylic acid monohydrate. [1] Like other fluoroquinolones, their mechanism of action involves the inhibition of bacterial DNA gyrase, which introduces negative supercoils into DNA. This study shows that fluoroquinolones, including T-3262, can inhibit DNA gyrase activity at low concentrations, while older generation quinolones such as pipemidic acid cannot achieve this effect. [1] No cross-resistance was observed between tosufloxacin tosylate hydrate (T-3262, A61827) and β-lactam or aminoglycoside antibiotics. However, partial cross-resistance was observed between fluoroquinolones and nalidixic acid, suggesting that they may share a common target enzyme. [1] This study suggests that tosufloxacin tosylate hydrate (T-3262, A61827) has broad-spectrum and potent in vitro and in vivo antibacterial activity, and therefore may be used clinically to treat a variety of bacterial infections. Its indications may extend beyond urinary tract infections treated with older generation quinolones to respiratory and soft tissue infections. [1] |
| Molecular Formula |
C26H25F3N4O7S
|
|---|---|
| Molecular Weight |
594.56
|
| Exact Mass |
594.14
|
| CAS # |
1400591-39-0
|
| Related CAS # |
Tosufloxacin;100490-36-6;Tosufloxacin tosylate;115964-29-9
|
| PubChem CID |
5282468
|
| Appearance |
White to off-white solid powder
|
| LogP |
5.062
|
| Hydrogen Bond Donor Count |
4
|
| Hydrogen Bond Acceptor Count |
14
|
| Rotatable Bond Count |
4
|
| Heavy Atom Count |
41
|
| Complexity |
915
|
| Defined Atom Stereocenter Count |
0
|
| InChi Key |
SSULTCPIIYRGFQ-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C19H15F3N4O3.C7H8O3S.H2O/c20-9-1-2-15(13(21)5-9)26-8-12(19(28)29)16(27)11-6-14(22)18(24-17(11)26)25-4-3-10(23)7-25;1-6-2-4-7(5-3-6)11(8,9)10;/h1-2,5-6,8,10H,3-4,7,23H2,(H,28,29);2-5H,1H3,(H,8,9,10);1H2
|
| Chemical Name |
7-(3-aminopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid;4-methylbenzenesulfonic acid;hydrate
|
| Synonyms |
A-61827 tosylate hydrateA61827 tosylate hydrateA 61827 tosylate hydrateT-3262T 3262
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO : ~12.5 mg/mL (~21.02 mM)
H2O : ~1 mg/mL (~1.68 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 1.25 mg/mL (2.10 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 1.25 mg/mL (2.10 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 1.25 mg/mL (2.10 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6819 mL | 8.4096 mL | 16.8192 mL | |
| 5 mM | 0.3364 mL | 1.6819 mL | 3.3638 mL | |
| 10 mM | 0.1682 mL | 0.8410 mL | 1.6819 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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