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Identification
Name Trovafloxacin
Accession Number DB00685 (APRD01281)
Type small molecule
Groups approved
Description

Trovafloxacin (sold as Trovan by Pfizer) is a broad spectrum antibiotic that inhibits the uncoiling of supercoiled DNA in various bacteria by blocking the activity of DNA gyrase and topoisomerase IV. It was withdrawn from the market due to the risk of hepatotoxicity. It had better gram-positive bacterial coverage and less gram-negative coverage than the previous fluoroquinolones. [Wikipedia]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Trovafloxacin mesylate
  • TVFX
Brand names
  • Trovan
Brand name mixtures
  • Trovan/Zithromax Compliance Pak (Trovafloxacin + Azithromycin)
Categories
  • Anti-Infective Agents
  • Anti-Infectives
  • Quinolones
  • Fluoroquinolones
CAS number 147059-72-1
Weight Average: 416.3533
Monoisotopic: 416.109624981
Chemical Formula C20H15F3N4O3
InChI Key InChIKey=WVPSKSLAZQPAKQ-SOSAQKQKSA-N
InChI
InChI=1S/C20H15F3N4O3/c21-8-1-2-15(13(22)3-8)27-7-12(20(29)30)17(28)9-4-14(23)19(25-18(9)27)26-5-10-11(6-26)16(10)24/h1-4,7,10-11,16H,5-6,24H2,(H,29,30)/t10-,11+,16?
Plain Text
IUPAC Name
7-[(1R,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
SMILES
[H][C@@]12CN(C[C@]1([H])C2N)C1=NC2=C(C=C1F)C(=O)C(=CN2C1=C(F)C=C(F)C=C1)C(O)=O
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Fluoroquinolones and Quinolones
Substructures
  • Hydroxy Compounds
  • Acetates
  • Aliphatic and Aryl Amines
  • Pyridines and Derivatives
  • Cyclopropane and Derivatives
  • Pyrrolidines
  • Benzene and Derivatives
  • Carboxylic Acids and Derivatives
  • Aminopyridines and Derivatives
  • Halobenzenes
  • Heterocyclic compounds
  • Aromatic compounds
  • Cyanamides
  • Aryl Halides
  • Anilines
  • Piperidines
  • Fluoroquinolones and Quinolones
Pharmacology
Indication For treatment of infections caused by susceptible strains of the designated microorganisms in uncomplicated urethral gonorrhea in males and endocervical and rectal gonorrhea in females caused by Neisseria gonorrhoeae as well as non gonoccocal urethritis and cervicitis due to Chlamydia trachomatis.
Pharmacodynamics Trovafloxacin is a broad spectrum antibiotic that inhibits DNA supercoiling in various bacteria by blocking the activity of DNA gyrase and topoisomerase IV. It is not used widely due to the risk of hepatotoxicity. It tends to have better gram-positive bacterial coverage and less gram-negative coverage than the previous fluoroquinolones. Mechanism of action of fluoroquinolones including trovafloxacin is different from that of penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines. Therefore fluoroquinolones may be active against pathogens that are resistant to these antibiotics. There is no cross-resistance between trovafloxacin and the mentioned classes of antibiotics. The overall results obtained from in vitro synergy studies, testing combinations of trovafloxacin with beta-lactams and aminoglycosides, indicate that synergy is strain specific and not commonly encountered. This agrees with results obtained previously with other fluoroquinolones. Resistance to trovafloxacin in vitro develops slowly via multiple-step mutation in a manner similar to other fluoroquinolones. Resistance to trovafloxacin in vitro occurs at a general frequency of between 1x10-7 to 10-10. Although cross-resistance has been observed between trovafloxacin and some other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to trovafloxacin.
Mechanism of action Trovafloxacin is a fluoronaphthyridone related to the fluoroquinolones with in vitro activity against a wide range of gram-negative and gram-positive aerobic and anaerobic microorganisms. The bactericidal action of trovafloxacin results from inhibition of DNA gyrase and topoisomerase IV. DNA gyrase is an essential enzyme that is involved in the replication, transcription, and repair of bacterial DNA. Topoisomerase IV is an enzyme known to play a key role in the partitioning of the chromosomal DNA during bacterial cell division.
Absorption Well-absorbed from the gastrointestinal tract after oral administration and does not depend on concomitant food intake. The absolute bioavailability is approximately 88%.
Volume of distribution Not Available
Protein binding The mean plasma protein bound fraction is approximately 76%, and is concentration-independent.
Metabolism

Metabolism Trovafloxacin is metabolized by conjugation (the role of cytochrome P450 oxidative metabolism of trovafloxacin is minimal). The major metabolites include the ester glucuronide, which appears in the urine (13% of the administered dose); and the N -acetyl metabolite, which appears in the feces and serum (9% and 2.5% of the administered dose, respectively). Other minor metabolites include diacid, hydroxycarboxylic acid, and sulfamate, which have been identified in both the feces and the urine in small amounts (< 4% of the administered dose).
Route of elimination Approximately 50% of an oral dose is excreted unchanged (43% in the feces and 6% in the urine).
Half life Following oral administration, half-life ranged from 9.1 hours to 12.2 hours over the dosage range of 100 to 200 mg tablets. Following intravenous infusion, half-life ranged from 9.4 to 12.7 hours over a dosage range of 100 to 300 mg.
Clearance Not Available
Toxicity Symptoms of overdose include convulsions, decreased activity, diarrhea, sleepiness, tremors, and/or vomiting.
Affected organisms
  • Enteric bacteria and other eubacteria
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Pfizer chemicals div pfizer inc
  • Pfizer central research
Packagers
Dosage forms
Form Route Strength
Liquid Intravenous
Tablet Oral
Prices Not Available
Patents
Country Patent Number Approved Expires
United States 6187341 1999-01-20 2019-01-20
United States 5164402 1992-11-17 2009-11-17
Canada 2023217 1996-12-10 2010-08-14
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
water solubility 12.3 mg/L PhysProp
logP 3.7 PhysProp
Predicted Properties
Property Value Source
water solubility 7.04e-02 g/l ALOGPS
logP 0.86 ALOGPS
logP -1.53 ChemAxon Molconvert
logS -3.77 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 7 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 99.76 ChemAxon Molconvert
rotatable bond count 3 ChemAxon Molconvert
refractivity 101.04 ChemAxon Molconvert
polarizability 38.34 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Compound C07664 Link_out
PubChem Compound 62959 Link_out
PubChem Substance 46508751 Link_out
ChemSpider 56670 Link_out
BindingDB 50146361 Link_out
Therapeutic Targets Database DAP000652 Link_out
PharmGKB PA451804 Link_out
Drug Product Database 2239191 Link_out
RxList http://www.rxlist.com/cgi/generic/trovazit.htm Link_out
Drugs.com http://www.drugs.com/mtm/trovafloxacin.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Trovafloxacin Link_out
ATC Codes
  • J01MA13
AHFS Codes Not Available
PDB Entries Not Available
FDA label Not Available
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. DNA gyrase subunit A

Pharmacological action: yes
Actions: inhibitor

DNA gyrase negatively supercoils closed circular double- stranded DNA in an ATP-dependent manner and also catalyzes the interconversion of other topological isomers of double-stranded DNA rings, including catenanes and knotted rings

Organism class: bacterial
UniProt ID: P43700 Link_out
Gene: gyrA
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Brisse S, Milatovic D, Fluit AC, Verhoef J, Martin N, Scheuring S, Kohrer K, Schmitz FJ: Comparative in vitro activities of ciprofloxacin, clinafloxacin, gatifloxacin, levofloxacin, moxifloxacin, and trovafloxacin against Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter cloacae, and Enterobacter aerogenes clinical isolates with alterations in GyrA and ParC proteins. Antimicrob Agents Chemother. 1999 Aug;43(8):2051-5. Pubmed
  4. Bebear CM, Grau O, Charron A, Renaudin H, Gruson D, Bebear C: Cloning and nucleotide sequence of the DNA gyrase (gyrA) gene from Mycoplasma hominis and characterization of quinolone-resistant mutants selected in vitro with trovafloxacin. Antimicrob Agents Chemother. 2000 Oct;44(10):2719-27. Pubmed
  5. Gootz TD, Zaniewski RP, Haskell SL, Kaczmarek FS, Maurice AE: Activities of trovafloxacin compared with those of other fluoroquinolones against purified topoisomerases and gyrA and grlA mutants of Staphylococcus aureus. Antimicrob Agents Chemother. 1999 Aug;43(8):1845-55. Pubmed

2. DNA topoisomerase 4 subunit A

Pharmacological action: yes
Actions: inhibitor

Topoisomerase IV is essential for chromosome segregation. It has relaxation of supercoiled DNA activity. Performs the decatenation events required during the replication of a circular DNA molecule

Organism class: bacterial
UniProt ID: P43702 Link_out
Gene: parC
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Rafii F, Park M, Novak JS: Alterations in DNA gyrase and topoisomerase IV in resistant mutants of Clostridium perfringens found after in vitro treatment with fluoroquinolones. Antimicrob Agents Chemother. 2005 Feb;49(2):488-92. Pubmed
  4. Daporta MT, Munoz Bellido JL, Guirao GY, Hernandez MS, Garcia-Rodriguez JA: In vitro activity of older and newer fluoroquinolones against efflux-mediated high-level ciprofloxacin-resistant Streptococcus pneumoniae. Int J Antimicrob Agents. 2004 Aug;24(2):185-7. Pubmed
  5. Ruiz J, Jurado A, Garcia-Mendez E, Marco F, Aguilar L, Jimenez de Anta MT, Vila J: Frequency of selection of fluoroquinolone-resistant mutants of Neisseria gonorrhoeae exposed to gemifloxacin and four other quinolones. J Antimicrob Chemother. 2001 Oct;48(4):545-8. Pubmed

3. DNA topoisomerase 2-alpha

Pharmacological action: unknown
Actions: inhibitor

Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks

Organism class: human
UniProt ID: P11388 Link_out
Gene: TOP2A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on November 10, 2010 13:41

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.