Identification

Name
Cinoxacin
Accession Number
DB00827  (APRD00873)
Type
Small Molecule
Groups
Approved, Investigational, Withdrawn
Description

Synthetic antimicrobial related to oxolinic acid and nalidixic acid and used in urinary tract infections.

Structure
Thumb
Synonyms
  • 1-ethyl-6,7-methylenedioxy-4(1H)-oxocinnoline-3-carboxylic acid
  • 5-Ethyl-8-oxo-5,8-dihydro-1,3-dioxa-5,6-diaza-cyclopenta[b]naphthalene-7-carboxylic acid
  • Cinoxacin
  • Cinoxacine
  • Cinoxacino
  • Cinoxacinum
External IDs
64716
International/Other Brands
Cinobac (Oclassen) / Mecicon (Chung Mei) / Tatsulexin (Tatsumi Kagaku) / Urocinox (BioHealth Pharmaceuticals)
Categories
UNII
LMK22VUH23
CAS number
28657-80-9
Weight
Average: 262.2182
Monoisotopic: 262.05897144
Chemical Formula
C12H10N2O5
InChI Key
VDUWPHTZYNWKRN-UHFFFAOYSA-N
InChI
InChI=1S/C12H10N2O5/c1-2-14-7-4-9-8(18-5-19-9)3-6(7)11(15)10(13-14)12(16)17/h3-4H,2,5H2,1H3,(H,16,17)
IUPAC Name
1-ethyl-4-oxo-1H,4H,7H-[1,3]dioxolo[4,5-g]cinnoline-3-carboxylic acid
SMILES
CCN1N=C(C(O)=O)C(=O)C2=CC3=C(OCO3)C=C12

Pharmacology

Indication

For the treatment of initial and recurrent urinary tract infections in adults caused by the following susceptible microorganisms: Escherichia coli, Proteus mirabilis, Proteus vulgaris, Klebsiella species (including K. pneumoniae), and Enterobacter species.

Pharmacodynamics

Cinoxacin is a synthetic antibacterial agent with in vitro activity against many gram-negative aerobic bacteria, particularly strains of the Enterobacteriaceae family. Cinoxacin inhibits bacterial deoxyribonucleic acid (DNA) synthesis, is bactericidal, and is active over the entire urinary pH range. Cross resistance with nalidixic acid has been demonstrated.

Mechanism of action

Evidence exists that cinoxacin binds strongly, but reversibly, to DNA, interfering with synthesis of RNA and, consequently, with protein synthesis. It appears to also inhibit DNA gyrase. This enzyme is necessary for proper replicated DNA separation. By inhibiting this enzyme, DNA replication and cell division is inhibited.

TargetActionsOrganism
ADNA gyrase subunit A
inhibitor
Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd)
UDNA
intercalation
Human
Absorption

Rapidly absorbed after oral administration. The presence of food delays absorption but does does not affect total absorption.

Volume of distribution
Not Available
Protein binding

60 to 80%

Metabolism

Hepatic, with approximately 30-40% metabolized to inactive metabolites.

Route of elimination
Not Available
Half life

The mean serum half-life is 1.5 hours. Half-life in patients with impaired renal function may exceed 10 hours.

Clearance
Not Available
Toxicity

Oral, subcutaneous, and intravenous LD50 in the rat is 3610 mg/kg, 1380 mg/kg, and 860 mg/kg, respectively. Oral, subcutaneous, and intravenous LD50 in the mouse is 2330 mg/kg, 900 mg/kg, and 850 mg/kg, respectively.Symptoms following an overdose of cinoxacin may include anorexia, nausea, vomiting, epigastric distress, and diarrhea. The severity of the epigastric distress and the diarrhea are dose related. Headache, dizziness, insomnia, photophobia, tinnitus, and a tingling sensation have been reported in some patients.

Affected organisms
  • Enteric bacteria and other eubacteria
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe therapeutic efficacy of (R)-warfarin can be increased when used in combination with Cinoxacin.
(S)-WarfarinThe therapeutic efficacy of (S)-Warfarin can be increased when used in combination with Cinoxacin.
2,4-thiazolidinedioneThe therapeutic efficacy of 2,4-thiazolidinedione can be increased when used in combination with Cinoxacin.
3-isobutyl-1-methyl-7H-xanthineThe metabolism of 3-isobutyl-1-methyl-7H-xanthine can be decreased when combined with Cinoxacin.
4-hydroxycoumarinThe therapeutic efficacy of 4-hydroxycoumarin can be increased when used in combination with Cinoxacin.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Cinoxacin.
7-DeazaguanineThe metabolism of 7-Deazaguanine can be decreased when combined with Cinoxacin.
7,9-DimethylguanineThe metabolism of 7,9-Dimethylguanine can be decreased when combined with Cinoxacin.
8-azaguanineThe metabolism of 8-azaguanine can be decreased when combined with Cinoxacin.
8-chlorotheophyllineThe metabolism of 8-chlorotheophylline can be decreased when combined with Cinoxacin.
Food Interactions
Not Available

References

Synthesis Reference

White, W.A.; U.S. Patent 3,669,965; June 13, 1972; assigned to Eli Lilly & Company.

US3669965
General References
Not Available
External Links
Human Metabolome Database
HMDB0014965
KEGG Drug
D00872
KEGG Compound
C08052
PubChem Compound
2762
PubChem Substance
46507547
ChemSpider
2660
BindingDB
39350
ChEBI
3716
ChEMBL
CHEMBL1208
Therapeutic Targets Database
DAP000999
PharmGKB
PA449007
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Cinoxacin
ATC Codes
J01MB06 — Cinoxacin
FDA label
Download (37.2 KB)
MSDS
Download (53.7 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0RecruitingTreatmentOsteomyelitis1

Pharmacoeconomics

Manufacturers
  • Eli lilly and co
  • Teva pharmaceuticals usa inc
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)261-262White, W.A.; U.S. Patent 3,669,965; June 13, 1972; assigned to Eli Lilly & Company.
logP1.5Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.961 mg/mLALOGPS
logP1.25ALOGPS
logP1.72ChemAxon
logS-2.4ALOGPS
pKa (Strongest Acidic)4.93ChemAxon
pKa (Strongest Basic)-4.6ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area88.43 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity73.6 m3·mol-1ChemAxon
Polarizability24.72 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9902
Blood Brain Barrier+0.7001
Caco-2 permeable-0.515
P-glycoprotein substrateNon-substrate0.5087
P-glycoprotein inhibitor INon-inhibitor0.8358
P-glycoprotein inhibitor IINon-inhibitor0.8382
Renal organic cation transporterNon-inhibitor0.7213
CYP450 2C9 substrateNon-substrate0.8137
CYP450 2D6 substrateNon-substrate0.8119
CYP450 3A4 substrateNon-substrate0.5503
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6
Ames testAMES toxic0.9106
CarcinogenicityNon-carcinogens0.8656
BiodegradationNot ready biodegradable0.8917
Rat acute toxicity1.8922 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8812
hERG inhibition (predictor II)Non-inhibitor0.9074
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 GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-00kr-2930000000-d8548621f53001ee222d

Taxonomy

Description
This compound belongs to the class of organic compounds known as cinnolines. These are organic aromatic compounds containing a benzene fused to a pyridazine ring.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazanaphthalenes
Sub Class
Benzodiazines
Direct Parent
Cinnolines
Alternative Parents
Benzodioxoles / Pyridazines and derivatives / Benzenoids / Vinylogous amides / Heteroaromatic compounds / Oxacyclic compounds / Monocarboxylic acids and derivatives / Carboxylic acids / Azacyclic compounds / Acetals
show 4 more
Substituents
Cinnoline / Benzodioxole / Pyridazine / Benzenoid / Heteroaromatic compound / Vinylogous amide / Oxacycle / Azacycle / Acetal / Monocarboxylic acid or derivatives
show 10 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
oxacycle, oxo carboxylic acid, cinnolines (CHEBI:3716)

Targets

Kind
Protein
Organism
Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd)
Pharmacological action
Yes
Actions
Inhibitor
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. Jariyawat S, Sekine T, Takeda M, Apiwattanakul N, Kanai Y, Sophasan S, Endou H: The interaction and transport of beta-lactam antibiotics with the cloned rat renal organic anion transporter 1. J Pharmacol Exp Ther. 1999 Aug;290(2):672-7. [PubMed:10411577]
  2. Drlica K, Zhao X: DNA gyrase, topoisomerase IV, and the 4-quinolones. Microbiol Mol Biol Rev. 1997 Sep;61(3):377-92. [PubMed:9293187]
  3. Neugebauer U, Szeghalmi A, Schmitt M, Kiefer W, Popp J, Holzgrabe U: Vibrational spectroscopic characterization of fluoroquinolones. Spectrochim Acta A Mol Biomol Spectrosc. 2005 May;61(7):1505-17. [PubMed:15820884]
  4. Tuma J, Connors WH, Stitelman DH, Richert C: On the effect of covalently appended quinolones on termini of DNA duplexes. J Am Chem Soc. 2002 Apr 24;124(16):4236-46. [PubMed:11960452]
2. DNA
Kind
Nucleotide
Organism
Human
Pharmacological action
Unknown
Actions
Intercalation
General Function:
Used for biological information storage.
Specific Function:
DNA contains the instructions needed for an organism to develop, survive and reproduce.
Molecular Weight:
2.15 x 1012 Da
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:17139284]
  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:17016423]
  3. Tuma J, Connors WH, Stitelman DH, Richert C: On the effect of covalently appended quinolones on termini of DNA duplexes. J Am Chem Soc. 2002 Apr 24;124(16):4236-46. [PubMed:11960452]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
Curator comments
This drug is a fluoroquinolone, and these agents are known to inhibit CYP1A2.
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Zhang L, Wei MJ, Zhao CY, Qi HM: Determination of the inhibitory potential of 6 fluoroquinolones on CYP1A2 and CYP2C9 in human liver microsomes. Acta Pharmacol Sin. 2008 Dec;29(12):1507-14. doi: 10.1111/j.1745-7254.2008.00908.x. [PubMed:19026171]
  2. Shahzadi A, Javed I, Aslam B, Muhammad F, Asi MR, Ashraf MY, Zia-ur-Rahman: Therapeutic effects of ciprofloxacin on the pharmacokinetics of carbamazepine in healthy adult male volunteers. Pak J Pharm Sci. 2011 Jan;24(1):63-8. [PubMed:21190921]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
Gene Name
SLC22A6
Uniprot ID
Q4U2R8
Uniprot Name
Solute carrier family 22 member 6
Molecular Weight
61815.78 Da
References
  1. Jariyawat S, Sekine T, Takeda M, Apiwattanakul N, Kanai Y, Sophasan S, Endou H: The interaction and transport of beta-lactam antibiotics with the cloned rat renal organic anion transporter 1. J Pharmacol Exp Ther. 1999 Aug;290(2):672-7. [PubMed:10411577]

Drug created on June 13, 2005 07:24 / Updated on December 16, 2018 06:43