Ethionamide

Identification

Name
Ethionamide
Accession Number
DB00609  (APRD00961)
Type
Small Molecule
Groups
Approved
Description

A second-line antitubercular agent that inhibits mycolic acid synthesis. It also may be used for treatment of leprosy. (From Smith and Reynard, Textbook of Pharmacology, 1992, p868)

Structure
Thumb
Synonyms
  • 2-Ethyl-4-thiopyridylamide
  • 2-ethylthioisonicotinamide
  • ETH
  • Ethinamide
  • Ethionamide
  • Ethionamidum
  • Ethioniamide
  • Ethylisothiamide
  • Ethyonomide
  • Etionamid
  • Etionamida
  • Etionamide
  • Etioniamid
  • ETP
External IDs
1314 TH / 1314-TH / Bayer 5312 / NSC-255115
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
TrecatorTablet, film coated250 mg/1OralWyeth Pharmaceuticals Inc., a subsidiary of Pfizer Inc.2004-11-08Not applicableUs
International/Other Brands
Ethatyl (Sanofi) / Ethide (Lupin) / Ethiokox (Radicura) / Ethomid (Vesalius Pharma) / Etionamida (AC Farma) / Etomid (Macleods) / Eton (Umeda) / Etyomid (Koçak) / Myobid (Panacea) / Trecator / Trecator-SC / Tubermin (Meiji Seika Kaisha)
Categories
UNII
OAY8ORS3CQ
CAS number
536-33-4
Weight
Average: 166.243
Monoisotopic: 166.05646902
Chemical Formula
C8H10N2S
InChI Key
AEOCXXJPGCBFJA-UHFFFAOYSA-N
InChI
InChI=1S/C8H10N2S/c1-2-7-5-6(8(9)11)3-4-10-7/h3-5H,2H2,1H3,(H2,9,11)
IUPAC Name
2-ethylpyridine-4-carbothioamide
SMILES
CCC1=NC=CC(=C1)C(N)=S

Pharmacology

Indication

For use in the treatment of pulmonary and extrapulmonary tuberculosis when other antitubercular drugs have failed.

Structured Indications
Pharmacodynamics

Ethinamate is bacteriostatic against M. tuberculosis. In a study examining ethionamide resistance, ethionamide administered orally initially decreased the number of culturable Mycobacterium tuberculosis organisms from the lungs of H37Rv infected mice. Drug resistance developed with continued ethionamide monotherapy, but did not occur when mice received ethionamide in combination with streptomycin or isoniazid.

Mechanism of action

Ethionamide may be bacteriostatic or bactericidal in action, depending on the concentration of the drug attained at the site of infection and the susceptibility of the infecting organism. Ethionamide, like prothionamide and pyrazinamide, is a nicotinic acid derivative related to isoniazid. It is thought that ethionamide undergoes intracellular modification and acts in a similar fashion to isoniazid. Isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall. Specifically isoniazid inhibits InhA, the enoyl reductase from Mycobacterium tuberculosis, by forming a covalent adduct with the NAD cofactor. It is the INH-NAD adduct that acts as a slow, tight-binding competitive inhibitor of InhA.

TargetActionsOrganism
UCatalase-peroxidase
other/unknown
Mycobacterium tuberculosis
AEnoyl-[acyl-carrier-protein] reductase [NADH]
adduct
Mycobacterium tuberculosis
Absorption

Essentially completely absorbed following oral administration and not subjected to any appreciable first pass metabolism. Bioavailability approximately 100%.

Volume of distribution
  • 93.5 L [healthy volunteers]
Protein binding

Approximately 30% bound to proteins.

Metabolism

Hepatic and extensive. Metabolized to the active metabolite sulfoxide, and several inactive metabolites. The sulphoxide metabolite has been demonstrated to have antimicrobial activity against Mycobacterium tuberculosis.

Route of elimination

Less than 1% of the oral dose is excreted as ethionamide in urine. Ethionamide is extensively metabolized to active and inactive metabolites.

Half life

2 to 3 hours

Clearance
Not Available
Toxicity

Symptoms of overdose include convulsions, nausea, and vomiting.

Affected organisms
  • Mycobacteria
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
BCG vaccineThe therapeutic efficacy of BCG vaccine can be decreased when used in combination with Ethionamide.Investigational
CycloserineThe risk or severity of adverse effects can be increased when Ethionamide is combined with Cycloserine.Approved
EthanolThe risk or severity of adverse effects can be increased when Ethanol is combined with Ethionamide.Approved
IsoniazidThe serum concentration of Isoniazid can be increased when it is combined with Ethionamide.Approved
Picosulfuric acidThe therapeutic efficacy of Picosulfuric acid can be decreased when used in combination with Ethionamide.Approved
Food Interactions
Not Available

References

Synthesis Reference

Chimie et Atomistique, France: British Patent 800,250: August 20, 1958.

General References
Not Available
External Links
Human Metabolome Database
HMDB14747
KEGG Drug
D00591
KEGG Compound
C07665
PubChem Compound
2761171
PubChem Substance
46506077
ChemSpider
2041901
ChEBI
4885
ChEMBL
CHEMBL1441
Therapeutic Targets Database
DAP001141
PharmGKB
PA164768738
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Ethionamide
ATC Codes
J04AD03 — Ethionamide
FDA label
Download (79.3 KB)
MSDS
Download (50.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0RecruitingTreatmentOsteomyelitis1
2, 3RecruitingTreatmentExtensively-drug Resistant Tuberculosis / Tuberculosis / Tuberculosis, Multidrug Resistant1
4RecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections1
Not AvailableCompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Tuberculosis1

Pharmacoeconomics

Manufacturers
  • Wyeth pharmaceuticals inc
Packagers
Dosage forms
FormRouteStrength
Tablet, film coatedOral250 mg/1
Prices
Unit descriptionCostUnit
Trecator 250 mg tablet4.31USD tablet
Trecator-SC 250 mg tablet3.21USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)166Chimie et Atomistique, France: British Patent 800,250: August 20, 1958.
water solubilityPractically insolubleNot Available
logP0.5Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.839 mg/mLALOGPS
logP1.88ALOGPS
logP1.33ChemAxon
logS-2.3ALOGPS
pKa (Strongest Acidic)11.89ChemAxon
pKa (Strongest Basic)5ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count1ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area38.91 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity50.19 m3·mol-1ChemAxon
Polarizability17.99 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9797
Blood Brain Barrier+0.9476
Caco-2 permeable+0.6962
P-glycoprotein substrateNon-substrate0.7714
P-glycoprotein inhibitor INon-inhibitor0.9646
P-glycoprotein inhibitor IINon-inhibitor1.0
Renal organic cation transporterNon-inhibitor0.8178
CYP450 2C9 substrateNon-substrate0.8459
CYP450 2D6 substrateNon-substrate0.7439
CYP450 3A4 substrateNon-substrate0.8278
CYP450 1A2 substrateInhibitor0.9107
CYP450 2C9 inhibitorNon-inhibitor0.907
CYP450 2D6 inhibitorNon-inhibitor0.923
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7557
Ames testNon AMES toxic0.9132
CarcinogenicityNon-carcinogens0.8337
BiodegradationNot ready biodegradable0.994
Rat acute toxicity2.1316 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9735
hERG inhibition (predictor II)Non-inhibitor0.9115
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-QQ , negativeLC-MS/MSsplash10-014i-0900000000-66bf96cc96715b3d5326
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-014i-1900000000-afd158837fc707e8fb01
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-0a4i-9200000000-dcd5e9f885fdaa4b6be0
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-0a4i-9000000000-10fa8785304c67e3f37c
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-0a4i-9000000000-78e21f4e886c1dbc2f13
MS/MS Spectrum - , positiveLC-MS/MSsplash10-014i-0900000000-4f9e673cda59e1bc62ee

Taxonomy

Description
This compound belongs to the class of organic compounds known as pyridines and derivatives. These are compounds containing a pyridine ring, which is a six-member aromatic heterocycle which consists of one nitrogen atom and five carbon atoms.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Pyridines and derivatives
Sub Class
Not Available
Direct Parent
Pyridines and derivatives
Alternative Parents
Thioamides / Heteroaromatic compounds / Thiocarboxylic acid amides / Azacyclic compounds / Thiocarbonyl compounds / Organopnictogen compounds / Organonitrogen compounds / Hydrocarbon derivatives
Substituents
Pyridine / Heteroaromatic compound / Thioamide / Azacycle / Thiocarboxylic acid amide / Organic nitrogen compound / Organopnictogen compound / Hydrocarbon derivative / Thiocarbonyl group / Organosulfur compound
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
pyridines, thiocarboxamide (CHEBI:4885)

Targets

Kind
Protein
Organism
Mycobacterium tuberculosis
Pharmacological action
Unknown
Actions
Other/unknown
General Function
Bifunctional enzyme with both catalase and broad-spectrum peroxidase activity, oxidizing various electron donors including NADP(H) (PubMed:9006925, PubMed:18178143). Protects M.tuberculosis against toxic reactive oxygen species (ROS) including hydrogen peroxide as well as organic peroxides and thus contributes to its survival within host macrophages by countering the phagocyte oxidative burst (PubMed:8658136, PubMed:15165233). Also displays efficient peroxynitritase activity, which may help the bacterium to persist in macrophages (PubMed:10080924).
Specific Function
Catalase activity
Gene Name
katG
Uniprot ID
P9WIE5
Uniprot Name
Catalase-peroxidase
Molecular Weight
80604.275 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. Morlock GP, Metchock B, Sikes D, Crawford JT, Cooksey RC: ethA, inhA, and katG loci of ethionamide-resistant clinical Mycobacterium tuberculosis isolates. Antimicrob Agents Chemother. 2003 Dec;47(12):3799-805. [PubMed:14638486]
  4. Guo H, Seet Q, Denkin S, Parsons L, Zhang Y: Molecular characterization of isoniazid-resistant clinical isolates of Mycobacterium tuberculosis from the USA. J Med Microbiol. 2006 Nov;55(Pt 11):1527-31. [PubMed:17030912]
  5. Lavender C, Globan M, Sievers A, Billman-Jacobe H, Fyfe J: Molecular characterization of isoniazid-resistant Mycobacterium tuberculosis isolates collected in Australia. Antimicrob Agents Chemother. 2005 Oct;49(10):4068-74. [PubMed:16189082]
  6. DeBarber AE, Mdluli K, Bosman M, Bekker LG, Barry CE 3rd: Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9677-82. [PubMed:10944230]
Kind
Protein
Organism
Mycobacterium tuberculosis
Pharmacological action
Yes
Actions
Adduct
General Function
Enoyl-ACP reductase of the type II fatty acid syntase (FAS-II) system, which is involved in the biosynthesis of mycolic acids, a major component of mycobacterial cell walls (PubMed:25227413). Catalyzes the NADH-dependent reduction of the double bond of 2-trans-enoyl-[acyl-carrier protein], an essential step in the fatty acid elongation cycle of the FAS-II pathway (PubMed:7599116). Shows preference for long-chain fatty acyl thioester substrates (>C16), and can also use 2-trans-enoyl-CoAs as alternative substrates (PubMed:7599116). The mycobacterial FAS-II system utilizes the products of the FAS-I system as primers to extend fatty acyl chain lengths up to C56, forming the meromycolate chain that serves as the precursor for final mycolic acids (PubMed:25227413).
Specific Function
Enoyl-[acyl-carrier-protein] reductase (nadh) activity
Gene Name
inhA
Uniprot ID
P9WGR1
Uniprot Name
Enoyl-[acyl-carrier-protein] reductase [NADH]
Molecular Weight
28527.55 Da
References
  1. 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]
  2. Morlock GP, Metchock B, Sikes D, Crawford JT, Cooksey RC: ethA, inhA, and katG loci of ethionamide-resistant clinical Mycobacterium tuberculosis isolates. Antimicrob Agents Chemother. 2003 Dec;47(12):3799-805. [PubMed:14638486]
  3. Banerjee A, Dubnau E, Quemard A, Balasubramanian V, Um KS, Wilson T, Collins D, de Lisle G, Jacobs WR Jr: inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science. 1994 Jan 14;263(5144):227-30. [PubMed:8284673]
  4. Larsen MH, Vilcheze C, Kremer L, Besra GS, Parsons L, Salfinger M, Heifets L, Hazbon MH, Alland D, Sacchettini JC, Jacobs WR Jr: Overexpression of inhA, but not kasA, confers resistance to isoniazid and ethionamide in Mycobacterium smegmatis, M. bovis BCG and M. tuberculosis. Mol Microbiol. 2002 Oct;46(2):453-66. [PubMed:12406221]
  5. Vilcheze C, Weisbrod TR, Chen B, Kremer L, Hazbon MH, Wang F, Alland D, Sacchettini JC, Jacobs WR Jr: Altered NADH/NAD+ ratio mediates coresistance to isoniazid and ethionamide in mycobacteria. Antimicrob Agents Chemother. 2005 Feb;49(2):708-20. [PubMed:15673755]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Drug created on June 13, 2005 07:24 / Updated on November 07, 2017 01:40