Besifloxacin

Identification

Name
Besifloxacin
Accession Number
DB06771  (DB05862)
Type
Small Molecule
Groups
Approved
Description

Besifloxacin is a fourth generation fluoroquinolone-type opthalmic antibiotic for the treatment of bacterial conjunctivitis. FDA approved on May 28, 2009.

Structure
Thumb
Synonyms
Not Available
External IDs
ISV-403
Product Ingredients
IngredientUNIICASInChI Key
Besifloxacin hydrochloride7506A6J57T 405165-61-9PMQBICKXAAKXAY-HNCPQSOCSA-N
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
BesivanceSuspension6 mg/mLOphthalmicPhysicians Total Care, Inc.2011-07-13Not applicableUs
BesivanceSuspension6 mg/mLOphthalmicBauch & Lomb Incorporated2009-05-28Not applicableUs
BesivanceSuspension0.6 %OphthalmicBausch & Lomb Inc2010-01-27Not applicableCanada
BesivanceSuspension6 mg/mLOphthalmicA S Medication Solutions2009-05-282017-06-20Us
Approved Generic Prescription Products
Not Available
Approved Over the Counter Products
Not Available
Unapproved/Other Products
Not Available
International/Other Brands
Not Available
Brand mixtures
Not Available
Categories
UNII
BFE2NBZ7NX
CAS number
141388-76-3
Weight
Average: 393.84
Monoisotopic: 393.125547465
Chemical Formula
C19H21ClFN3O3
InChI Key
QFFGVLORLPOAEC-SNVBAGLBSA-N
InChI
InChI=1S/C19H21ClFN3O3/c20-15-16-12(18(25)13(19(26)27)9-24(16)11-4-5-11)7-14(21)17(15)23-6-2-1-3-10(22)8-23/h7,9-11H,1-6,8,22H2,(H,26,27)/t10-/m1/s1
IUPAC Name
7-[(3R)-3-aminoazepan-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
SMILES
N[[email protected]@H]1CCCCN(C1)C1=C(F)C=C2C(=O)C(=CN(C3CC3)C2=C1Cl)C(O)=O

Pharmacology

Indication

Treatment of bacterial conjunctivitis. Bacterial isolates that are susceptible to besifloxacin include: CDC coryneform group G; Corynebacterium pseudodiphtheriticum; Corynebacterium striatum; Haemophilus influenzae; Moraxella lacunata; Staphylococcus aureus; Staphylococcus epidermidis; Staphylococcus hominis; Staphylococcus lugdunensis; Streptococcus mitis group; Streptococcus oralis; Streptococcus pneumoniae; Streptococcus salivarius*

Structured Indications
Pharmacodynamics

Besifloxacin tear concentrations were higher than MIC90 (minimum inhibitory concentration) values for common bacterial pathogens and sustained for 24 hours or longer. Mean residence time in the conjunctiva was 4.7 hours.

Mechanism of action

Besifloxacin is a bactericidal fluroquinolone-type antibiotic that inhibits bacterial enzymes, DNA gyrase and topoisomerase IV. By inhibiting DNA gyrase, DNA replication, transcription, and repair is impaired. By inhibiting topoisomerase IV, decatenation during cell devision is impaired. Inhibiting these two targets also slows down development of resistance.

TargetActionsOrganism
ADNA topoisomerase 4 subunit A
antagonist
Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd)
ADNA topoisomerase 4 subunit A
antagonist
Streptococcus pneumoniae serotype 4 (strain ATCC BAA-334 / TIGR4)
ADNA gyrase subunit A
antagonist
Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd)
ADNA gyrase subunit A
antagonist
Streptococcus pneumoniae serotype 4 (strain ATCC BAA-334 / TIGR4)
Absorption

Although ocular surface concentrations are high, average systemic concentrtions after three-times daily dosing was less than 0.5 ng/mL. This indicates that besifloxacin is not appreciably absorbed into the systemic and has a very low risk of systemic side effects.

Volume of distribution

Not absorbed into the systemic

Protein binding

None

Metabolism

No appreciable metabolism

Route of elimination

N/A

Half life

The average elimination half-life of besifloxacin in plasma following multiple dosing was estimated to be 7 hours.

Clearance

N/A

Toxicity

LD50, rat: >2000 mg/kg. The most common adverse reaction reported in 2% of patients treated with besifloxacin was conjunctival redness.

Affected organisms
  • Gram negative and gram positive bacteria
  • Pseudomonas aeruginosa
  • Streptococcus pneumoniae
  • Haemophilus influenzae
  • Staphylococcus aureus
  • Aerococcus viridans
  • Corynebacterium sp. G
  • Corynebacterium pseudodiphtheriticum
  • Corynebacterium striatum
  • Moraxella catarrhalis
  • Moraxella lacunata
  • Staphylococcus epidermidis
  • Staphylococcus hominis
  • Staphylococcus lugdunensis
  • Staphylococcus warneri
  • Streptococcus mitis
  • Streptococcus oralis
  • Streptococcus salivarius
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Besifloxacin.Approved
BevacizumabBevacizumab may increase the cardiotoxic activities of Besifloxacin.Approved, Investigational
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Besifloxacin.Approved
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of Besifloxacin.Approved, Investigational
DeslanosideDeslanoside may decrease the cardiotoxic activities of Besifloxacin.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of Besifloxacin.Approved
DigoxinDigoxin may decrease the cardiotoxic activities of Besifloxacin.Approved
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with Besifloxacin.Approved, Investigational
OleandrinAnvirzel may decrease the cardiotoxic activities of Besifloxacin.Experimental
OuabainOuabain may decrease the cardiotoxic activities of Besifloxacin.Approved
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with Besifloxacin.Approved, Vet Approved
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Besifloxacin.Approved, Investigational
Food Interactions
Not Available

References

Synthesis Reference
Not Available
General References
  1. O'Brien TP: Besifloxacin ophthalmic suspension, 0.6%: a novel topical fluoroquinolone for bacterial conjunctivitis. Adv Ther. 2012 Jun;29(6):473-90. doi: 10.1007/s12325-012-0027-7. Epub 2012 Jun 20. [PubMed:22729919 ]
  2. Proksch JW, Granvil CP, Siou-Mermet R, Comstock TL, Paterno MR, Ward KW: Ocular pharmacokinetics of besifloxacin following topical administration to rabbits, monkeys, and humans. J Ocul Pharmacol Ther. 2009 Aug;25(4):335-44. doi: 10.1089/jop.2008.0116. [PubMed:19492955 ]
External Links
KEGG Drug
D08872
PubChem Compound
10178705
PubChem Substance
175427091
ChemSpider
8354210
ChEBI
135622
ChEMBL
CHEMBL1201760
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Besifloxacin
ATC Codes
S01AE08 — Besifloxacin
AHFS Codes
  • 52:04.04
PDB Entries
Not Available
FDA label
Download (148 KB)
MSDS
Download (159 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedScreeningCataract Extraction1
1CompletedScreeningHealthy Volunteers2
1CompletedTreatmentConjunctivitis, Bacterial1
2CompletedTreatmentConjunctivitis, Bacterial1
2TerminatedTreatmentUlcerative keratitis1
2, 3CompletedTreatmentConjunctivitis, Bacterial1
3CompletedTreatmentAcute Bacterial Conjunctivitis2
3CompletedTreatmentConjunctivitis, Bacterial1
3RecruitingTreatmentKeratitis; Infectious Disease (Manifestation)1
3TerminatedTreatmentConjunctivitis, Bacterial2
4CompletedNot AvailableCataract Extraction1
4CompletedNot AvailableCataract operation / Corneal Health1
4CompletedTreatmentBacterial blepharitis1
4Unknown StatusPreventionCataracts1
Not AvailableRecruitingTreatmentBacterial Keratitis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
SuspensionOphthalmic0.6 %
SuspensionOphthalmic6 mg/mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6685958 No2004-02-032021-06-20Us
US6699492 No2004-03-022019-03-31Us
US5447926 No1995-09-052012-09-05Us
US8415342 No2010-11-072030-11-07Us
US8937062 No2009-11-132029-11-13Us
US8481526 No2011-01-092031-01-09Us
US8604020 No2010-03-122030-03-12Us

Properties

State
Liquid
Experimental Properties
PropertyValueSource
water solubilityNot soluble in water MSDS
pKa6.0-7.0MSDS
Predicted Properties
PropertyValueSource
Water Solubility0.143 mg/mLALOGPS
logP0.7ALOGPS
logP0.54ChemAxon
logS-3.4ALOGPS
pKa (Strongest Acidic)5.64ChemAxon
pKa (Strongest Basic)9.67ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area86.87 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity101.75 m3·mol-1ChemAxon
Polarizability39 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9882
Blood Brain Barrier-0.9103
Caco-2 permeable-0.5689
P-glycoprotein substrateSubstrate0.8063
P-glycoprotein inhibitor INon-inhibitor0.8968
P-glycoprotein inhibitor IINon-inhibitor0.9584
Renal organic cation transporterNon-inhibitor0.7016
CYP450 2C9 substrateNon-substrate0.869
CYP450 2D6 substrateNon-substrate0.8319
CYP450 3A4 substrateNon-substrate0.6463
CYP450 1A2 substrateNon-inhibitor0.7511
CYP450 2C9 inhibitorNon-inhibitor0.8486
CYP450 2D6 inhibitorNon-inhibitor0.8295
CYP450 2C19 inhibitorNon-inhibitor0.7648
CYP450 3A4 inhibitorNon-inhibitor0.6834
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8053
Ames testAMES toxic0.742
CarcinogenicityNon-carcinogens0.8853
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.3263 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9278
hERG inhibition (predictor II)Non-inhibitor0.6497
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted LC-MS/MS Spectrum - 10V, PositivePredicted LC-MS/MSNot Available
Predicted LC-MS/MS Spectrum - 20V, PositivePredicted LC-MS/MSNot Available
Predicted LC-MS/MS Spectrum - 40V, PositivePredicted LC-MS/MSNot Available
Predicted LC-MS/MS Spectrum - 10V, NegativePredicted LC-MS/MSNot Available
Predicted LC-MS/MS Spectrum - 20V, NegativePredicted LC-MS/MSNot Available
Predicted LC-MS/MS Spectrum - 40V, NegativePredicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as quinoline carboxylic acids. These are quinolines in which the quinoline ring system is substituted by a carboxyl group at one or more positions.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Quinolines and derivatives
Sub Class
Quinoline carboxylic acids
Direct Parent
Quinoline carboxylic acids
Alternative Parents
Fluoroquinolones / Chloroquinolines / Aminoquinolines and derivatives / Hydroquinolones / Hydroquinolines / Pyridinecarboxylic acids / Dialkylarylamines / Azepanes / Aryl chlorides / Benzenoids
show 14 more
Substituents
Quinoline-3-carboxylic acid / Fluoroquinolone / Aminoquinoline / Dihydroquinolone / Chloroquinoline / Haloquinoline / Dihydroquinoline / Pyridine carboxylic acid or derivatives / Pyridine carboxylic acid / Dialkylarylamine
show 30 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd)
Pharmacological action
Yes
Actions
Antagonist
General Function
Dna topoisomerase type ii (atp-hydrolyzing) activity
Specific Function
Topoisomerase IV is essential for chromosome segregation. It relaxes supercoiled DNA. Performs the decatenation events required during the replication of a circular DNA molecule.
Gene Name
parC
Uniprot ID
P43702
Uniprot Name
DNA topoisomerase 4 subunit A
Molecular Weight
83366.24 Da
References
  1. Carter NJ, Scott LJ: Besifloxacin ophthalmic suspension 0.6%. Drugs. 2010;70(1):83-97. doi: 10.2165/11203820-000000000-00000. [PubMed:20030427 ]
Kind
Protein
Organism
Streptococcus pneumoniae serotype 4 (strain ATCC BAA-334 / TIGR4)
Pharmacological action
Yes
Actions
Antagonist
General Function
Dna topoisomerase type ii (atp-hydrolyzing) activity
Specific Function
Topoisomerase IV is essential for chromosome segregation. It relaxes supercoiled DNA. Performs the decatenation events required during the replication of a circular DNA molecule.
Gene Name
parC
Uniprot ID
P72525
Uniprot Name
DNA topoisomerase 4 subunit A
Molecular Weight
93132.2 Da
References
  1. Carter NJ, Scott LJ: Besifloxacin ophthalmic suspension 0.6%. Drugs. 2010;70(1):83-97. doi: 10.2165/11203820-000000000-00000. [PubMed:20030427 ]
Kind
Protein
Organism
Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd)
Pharmacological action
Yes
Actions
Antagonist
General Function
Dna topoisomerase type ii (atp-hydrolyzing) activity
Specific Function
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, inc...
Gene Name
gyrA
Uniprot ID
P43700
Uniprot Name
DNA gyrase subunit A
Molecular Weight
97817.145 Da
References
  1. Carter NJ, Scott LJ: Besifloxacin ophthalmic suspension 0.6%. Drugs. 2010;70(1):83-97. doi: 10.2165/11203820-000000000-00000. [PubMed:20030427 ]
Kind
Protein
Organism
Streptococcus pneumoniae serotype 4 (strain ATCC BAA-334 / TIGR4)
Pharmacological action
Yes
Actions
Antagonist
General Function
Dna topoisomerase type ii (atp-hydrolyzing) activity
Specific Function
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, inc...
Gene Name
gyrA
Uniprot ID
P72524
Uniprot Name
DNA gyrase subunit A
Molecular Weight
92052.595 Da
References
  1. Carter NJ, Scott LJ: Besifloxacin ophthalmic suspension 0.6%. Drugs. 2010;70(1):83-97. doi: 10.2165/11203820-000000000-00000. [PubMed:20030427 ]
Drug created on September 14, 2010 10:21 / Updated on September 01, 2017 11:30