ETHIONAMIDE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C8H10N2S
Molecular Weight	166.243
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CCC1=NC=CC(=C1)C(N)=S

InChI

InChIKey=AEOCXXJPGCBFJA-UHFFFAOYSA-N

InChI=1S/C8H10N2S/c1-2-7-5-6(8(9)11)3-4-10-7/h3-5H,2H2,1H3,(H2,9,11)

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/013026s024lbl.pdf
Curator's Comment: Description was created using several sources including: http://www.ncbi.nlm.nih.gov/pubmed/13741471; https://www.ncbi.nlm.nih.gov/pubmed/17220416; http://www.ncbi.nlm.nih.gov/pubmed/26435990

Ethionamide is a second-line agent, structurally similar to isoniazid, used as a second-line therapy for the treatment of multidrug-resistant tuberculosis or active tuberculosis in case of patient intolerance to other drugs. Depending on its the concentration at the infected site and the susceptibility of the infecting organism it may be bacteriostatic or bactericidal. When used alone rapidly develops bacterial resistance. Ethionamide was approved by FDA in 1965 as TRECATOR manufactured by Wyeth Pharmaceuticals Inc. (purchased by Pfizer in 2009). Ethionamide is specific for Mycobacteria and is thought to exert a toxic effect on mycolic acid components of the bacterial cell wall when activated through intermediate S-oxidation by EtaA. Mycolic acid synthesis was shown to be inhibited by ethionamide in the EthA protein-overexpressing mycobacteria,

CNS Activity

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Catalase-peroxidase 3 Target ID: P9WIE5\|\|\|Q50553 Gene ID: 885638.0 Gene Symbol: katG Target Organism: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) Sources: http://www.drugbank.ca/drugs/DB00609	Substrate 661
Enoyl-[acyl-carrier-protein] reductase 5 Target ID: CHEMBL1849 Sources: http://www.ncbi.nlm.nih.gov/pubmed/10944230	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Tuberculosis 83 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/013026s024lbl.pdf	Curative		Approved 8429	TRECATOR Approved Use Trecator is primarily indicated for the treatment of active tuberculosis in patients with M. tuberculosis resistant to isoniazid or rifampin, or when there is intolerance on the part of the patient to other drugs. Its use alone in the treatment of tuberculosis results in the rapid development of resistance. It is essential, therefore, to give a suitable companion drug or drugs, the choice being based on the results of susceptibility tests. If the susceptibility tests indicate that the patient's organism is resistant to one of the first-line antituberculosis drugs (i.e., isoniazid or rifampin) yet susceptible to ethionamide, ethionamide should be accompanied by at least one drug to which the M. tuberculosis isolate is known to be susceptible.3 If the tuberculosis is resistant to both isoniazid and rifampin, yet susceptible to ethionamide, ethionamide should be accompanied by at least two other drugs to which the M. tuberculosis isolate is known to be susceptible.3 Patient nonadherence to prescribed treatment can result in treatment failure and in the development of drug-resistant tuberculosis, which can be life-threatening and lead to other serious health risks. It is, therefore, essential that patients adhere to the drug regimen for the full duration of treatment. Directly observed therapy is recommended for all patients receiving treatment for tuberculosis. Patients in whom drug-resistant M. tuberculosis organisms are isolated should be managed in consultation with an expert in the treatment of drug-resistant tuberculosis. Launch Date -1.47484803E11

C_max

Value	Dose	Co-administered	Analyte	Population
2.16 μg/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/013026s024lbl.pdf	250 mg single, oral dose: 250 mg route of administration: Oral experiment type: SINGLE co-administered:		ETHIONAMIDE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
7.67 μg × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/013026s024lbl.pdf	250 mg single, oral dose: 250 mg route of administration: Oral experiment type: SINGLE co-administered:		ETHIONAMIDE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
1.92 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/013026s024lbl.pdf	250 mg single, oral dose: 250 mg route of administration: Oral experiment type: SINGLE co-administered:		ETHIONAMIDE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
70% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/013026s024lbl.pdf	250 mg single, oral dose: 250 mg route of administration: Oral experiment type: SINGLE co-administered:		ETHIONAMIDE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED

Doses

Dose	Population	Adverse events
0.1 g 2 times / week multiple, oral MTD Dose: 0.1 g, 2 times / week Route: oral Route: multiple Dose: 0.1 g, 2 times / week Co-administed with:: AMINOSALICYLATE SODIUM(6 g; oral; 2/week) ISONIAZID(15 mg/kg; oral; 2/week) Sources: https://pubmed.ncbi.nlm.nih.gov/4924649/	unhealthy, >12 n = 27 Health Status: unhealthy Condition: pulmonary tuberculosis Age Group: >12 Sex: M+F Population Size: 27 Sources: https://pubmed.ncbi.nlm.nih.gov/4924649/	Sources: https://pubmed.ncbi.nlm.nih.gov/4924649/
0.5 g 2 times / week multiple, oral MTD Dose: 0.5 g, 2 times / week Route: oral Route: multiple Dose: 0.5 g, 2 times / week Co-administed with:: AMINOSALICYLATE SODIUM(6 g; oral; 2/week) ISONIAZID(15 mg/kg; oral; 2/week) Sources: https://pubmed.ncbi.nlm.nih.gov/4924649/	unhealthy, >12 n = 27 Health Status: unhealthy Condition: pulmonary tuberculosis Age Group: >12 Sex: M+F Population Size: 27 Sources: https://pubmed.ncbi.nlm.nih.gov/4924649/	Sources: https://pubmed.ncbi.nlm.nih.gov/4924649/
0.75 g 2 times / week multiple, oral MTD Dose: 0.75 g, 2 times / week Route: oral Route: multiple Dose: 0.75 g, 2 times / week Co-administed with:: AMINOSALICYLATE SODIUM(6 g; oral; 2/week) ISONIAZID(15 mg/kg; oral; 2/week) Sources: https://pubmed.ncbi.nlm.nih.gov/4924649/	unhealthy, >12 n = 27 Health Status: unhealthy Condition: pulmonary tuberculosis Age Group: >12 Sex: M+F Population Size: 27 Sources: https://pubmed.ncbi.nlm.nih.gov/4924649/	Sources: https://pubmed.ncbi.nlm.nih.gov/4924649/
1.25 g 2 times / week multiple, oral MTD Dose: 1.25 g, 2 times / week Route: oral Route: multiple Dose: 1.25 g, 2 times / week Co-administed with:: AMINOSALICYLATE SODIUM(6 g; oral; 2/week) ISONIAZID(15 mg/kg; oral; 2/week) Sources: https://pubmed.ncbi.nlm.nih.gov/4924649/	unhealthy, >12 n = 27 Health Status: unhealthy Condition: pulmonary tuberculosis Age Group: >12 Sex: M+F Population Size: 27 Sources: https://pubmed.ncbi.nlm.nih.gov/4924649/	Sources: https://pubmed.ncbi.nlm.nih.gov/4924649/
1.5 g 2 times / week multiple, oral MTD Dose: 1.5 g, 2 times / week Route: oral Route: multiple Dose: 1.5 g, 2 times / week Co-administed with:: AMINOSALICYLATE SODIUM(6 g; oral; 2/week) ISONIAZID(15 mg/kg; oral; 2/week) Sources: https://pubmed.ncbi.nlm.nih.gov/4924649/	unhealthy, >12 n = 27 Health Status: unhealthy Condition: pulmonary tuberculosis Age Group: >12 Sex: M+F Population Size: 27 Sources: https://pubmed.ncbi.nlm.nih.gov/4924649/	Sources: https://pubmed.ncbi.nlm.nih.gov/4924649/

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2B6 810 CYP2C8 911 CYP2C19 1478 BCRP 699 OATP1B1 788

Drug as perpetrator

Target	Modality	Activity
CYP2C9 1819	inhibitor 3277 Sources: https://www.jstage.jst.go.jp/article/bpb/38/9/38_b15-00313/_pdf/-char/en#page=4 Page: 4.0	no
CYP2D6 1891	inhibitor 3277 Sources: https://www.jstage.jst.go.jp/article/bpb/38/9/38_b15-00313/_pdf/-char/en#page=4 Page: 4.0	no
OATP1B1 803	inhibitor 3277 Sources: https://web.archive.org/web/20210121185751/https://www.natap.org/2020/GLASGOW/GLASGOW_66.htm	weak
CYP2C8 965	inhibitor 3277 Sources: https://www.jstage.jst.go.jp/article/bpb/38/9/38_b15-00313/_pdf/-char/en#page=4 Page: 4.0	yes [IC50 110 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.jstage.jst.go.jp/article/bpb/38/9/38_b15-00313/_pdf/-char/en#page=4 Page: 4.0	yes [IC50 195 uM]
CYP2B6 1001	inhibitor 3277 Sources: https://www.jstage.jst.go.jp/article/bpb/38/9/38_b15-00313/_pdf/-char/en#page=4 Page: 4.0	yes [IC50 396 uM]
CYP1A2 1692	inhibitor 3277 Sources: https://www.jstage.jst.go.jp/article/bpb/38/9/38_b15-00313/_pdf/-char/en#page=4 Page: 4.0	yes [IC50 524 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4068461/	yes [IC50 78.4 uM]
BCRP 773	inhibitor 3277 Sources: https://web.archive.org/web/20210121185751/https://www.natap.org/2020/GLASGOW/GLASGOW_66.htm	yes

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:4885	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:4885
ChemicalBook	CB1292374	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB1292374
MolPort	MolPort-000-159-777	https://www.molport.com/shop/molecule-link/MolPort-000-159-777
Selleck Chemicals	Ethionamide	http://www.selleckchem.com/products/Ethionamide.html
ZINC	ZINC000003872520	http://zinc15.docking.org/substances/ZINC000003872520
eMolecules	538116	https://www.emolecules.com/cgi-bin/more?vid=538116

PubMed

Title	Date	PubMed
Spectrum of drugs against atypical mycobacteria: how valid is the current practice of drug susceptibility testing and the choice of drugs?	1992 Dec	1303690
Mycolic acid synthesis: a target for ethionamide in mycobacteria?	1992 Jun	1416831
Thiolactomycin and related analogues as novel anti-mycobacterial agents targeting KasA and KasB condensing enzymes in Mycobacterium tuberculosis.	2000 Jun 2	10747933
[Components of monitoring drug resistance of tuberculosis agent in the evaluation of effectiveness of the national tuberculosis control program].	2001	11490457
Ion interaction reagent reversed-phase high-performance liquid chromatography determination of anti-tuberculosis drugs and metabolites in biological fluids.	2001 Apr 25	11339291
High-performance liquid chromatographic-tandem mass spectrometric method for the determination of ethionamide in human plasma, bronchoalveolar lavage fluid and alveolar cells.	2001 Apr 5	11334350
[Treatment outcomes of multidrug-resistant tuberculosis--comparison between success and failure cases].	2001 Dec	11806128
Solvent effects on the thioamide rotational barrier: an experimental and theoretical study.	2001 Mar 7	11456827
Pharmacokinetics of para-aminosalicylic acid granules under four dosing conditions.	2001 Nov	11724078
[Two cases of multi-drug-resistant pulmonary tuberculosis with para-aminosalicylic acid (PAS)-induced hypothyroidism].	2001 Oct	11712388
Therapeutic drug monitoring in the treatment of tuberculosis.	2002	12381217
Comparative study on the use of solid media: Löwenstein-Jensen and Ogawa in the determination of anti-tuberculosis drug susceptibility.	2002	12356456
Long-term follow up of childhood tuberculous meningitis.	2002 Aug	12206617
2-Pyridinethiol/2-pyridinethione tautomeric equilibrium. A comparative experimental and computational study.	2002 Dec 13	12467429
Transition metal complexes with thiosemicarbazide-based ligands. XLIII. Chlorobis(3-methylisoemicarbazide-kappa(2)N(1),N(4))zinc(II) chloride.	2002 Jun	12050422
Feasibility and cost-effectiveness of standardised second-line drug treatment for chronic tuberculosis patients: a national cohort study in Peru.	2002 Jun 8	12076553
Direct sensitivity test of the MB/BacT system.	2002 Mar	12016454
Effects of thioamide substitutions on the conformation and stability of alpha- and 3(10)-helices.	2002 May 8	11982387
Identifying the sources of tuberculosis in young children: a multistate investigation.	2002 Nov	12453345
Molecular epidemiology of tuberculosis in a sentinel surveillance population.	2002 Nov	12453343
Heterocyclic benzazole derivatives with antimycobacterial in vitro activity.	2002 Nov 18	12392731
Overexpression of inhA, but not kasA, confers resistance to isoniazid and ethionamide in Mycobacterium smegmatis, M. bovis BCG and M. tuberculosis.	2002 Oct	12406221
Drugs that inhibit mycolic acid biosynthesis in Mycobacterium tuberculosis.	2002 Sep	12164478
Diversity in the oxidation of substrates by cytochrome P450 2D6: lack of an obligatory role of aspartate 301-substrate electrostatic bonding.	2002 Sep 10	12206675
The 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) assay as rapid colorimetric method for determination of antibiotic susceptibility of clinical Mycobacterium tuberculosis isolates in liquid medium.	2003	12908735
Vibrational study of the secondary thioamide function, the intramolecular resonance assisted and intermolecular hydrogen bonding in NN'-hydroxyalkyl dithiooxamides.	2003 Apr	12659905
Lepromatous leprosy in a heart transplant recipient.	2003 Dec	14629293
Activities of moxifloxacin alone and in combination with other antimicrobial agents against multidrug-resistant Mycobacterium tuberculosis infection in BALB/c mice.	2003 Jan	12499213
Vibrational characterization of the peptide bond.	2003 Jan 1	12509146
Vibrational characterization of the tertiary amide and thioamide group.	2003 Mar 1	12609634
Preparation of thioamide building blocks via microwave-promoted three-component kindler reactions.	2003 Mar-Apr	12625704
Pharmacokinetics and relative bioavailability of clofazimine in relation to food, orange juice and antacid.	2004	15525560
Synthesis and antimycobacterial activity of 1,2,4-triazole 3-benzylsulfanyl derivatives.	2004 Apr	15081345
Use of MGIT 960 for rapid quantitative measurement of the susceptibility of Mycobacterium tuberculosis complex to ciprofloxacin and ethionamide.	2004 Apr	14973155
Pharmacy data for tuberculosis surveillance and assessment of patient management.	2004 Aug	15496244
Antituberculous activity of some aryl semicarbazone derivatives.	2004 Aug 2	15225698
Synthesis and antibacterial activity of arylpiperazinyl oxazolidinones with diversification of the N-substituents.	2004 Aug 2	15225689
New agents active against Mycobacterium avium complex selected by molecular topology: a virtual screening method.	2004 Jan	14645324
Covalent binding of the 13C-labeled skin sensitizers 5-chloro-2-methylisothiazol-3-one (MCI) and 2-methylisothiazol-3-one (MI) to a model peptide and glutathione.	2004 Jan 19	14698160
Computational study of conformational preferences of thioamide-containing azaglycine peptides.	2004 Jan 30	14648616
Treatment and follow-up of HIV-negative multidrug-resistant tuberculosis patients in an infectious diseases reference hospital, Buenos Aires, Argentina.	2004 Jun	15182150
Drug susceptibility of Brazilian strains of Mycobacterium bovis using traditional and molecular techniques.	2004 Nov	15654433
Axially dissymmetric N-thioacylated (S)-(-)-1,1'-binaphthyl-2,2'-diamine ligands for copper-catalyzed asymmetric Michael addition of diethylzinc to alpha,beta-unsaturated ketone.	2004 Nov	15455445
Mycobacterium triplex pulmonary disease in immunocompetent host.	2004 Oct	15504279
Multidrug resistant miliary tuberculosis and Pott's disease in an immunocompetent patient.	2004 Oct	15494824
Structure of EthR in a ligand bound conformation reveals therapeutic perspectives against tuberculosis.	2004 Oct 22	15494316
Outcome of treatment of multidrug resistant tuberculosis.	2004 Sep	15524226
Altered NADH/NAD+ ratio mediates coresistance to isoniazid and ethionamide in mycobacteria.	2005 Feb	15673755
Electron transfer kinetics and mechanistic study of the thionicotinamide coordinated to the pentacyanoferrate(III)/(II) complexes: a model system for the in vitro activation of thioamides anti-tuberculosis drugs.	2005 Feb	15621268
Analysis of Mycobacterium tuberculosis isolates from treatment failure patients living in East Timor.	2005 Jan	15675555

Patents

Sample Use Guides

In Vivo Use Guide

15 to 20 mg/kg/day, administered once daily

Route of Administration: Oral

In Vitro Use Guide

Two standardized in vitro susceptibility methods are available for testing ethionamide against M. tuberculosis organisms. The modified proportion method (CDC or NCCLS M24-P) utilizes Middlebrook and Cohn 7H10 agar medium impregnated with ethionamide at a final concentration of 5.0 ug/mL. After 2 to 3 weeks of incubation, MIC99 values are calculated by comparing the quantity of organisms growing in the medium containing drug to the control cultures. Mycobacterial growth in the presence of drug, of at least 1% of the growth in the control culture, indicates resistance.

Name

Type

Language

ETHIONAMIDE

Official Name

English

ETHIONAMIDE [VANDF]

Common Name

English

ethionamide [INN]

Common Name

English

ETHIONAMIDE [HSDB]

Common Name

English

ETHIONAMIDE [IARC]

Common Name

English

ETHIONAMIDE [MI]

Common Name

English

ETHIONAMIDE [EP MONOGRAPH]

Common Name

English

ETHIONAMIDE [ORANGE BOOK]

Common Name

English

TRECATOR

Brand Name

English

ETHIONAMIDE [JAN]

Common Name

English

ETHIONAMIDE [USAN]

Common Name

English

1314-TH

Code

English

TRECATOR-SC

Brand Name

English

4-PYRIDINECARBOTHIOAMIDE, 2-ETHYL-

Systematic Name

English

1314 TH

Code

English

ETHIONAMIDE [USP MONOGRAPH]

Common Name

English

ETHIONAMIDUM [WHO-IP LATIN]

Common Name

English

BAYER 5312

Code

English

2-Ethylthioisonicotinamide

Systematic Name

English

ETHIONAMIDE [USP-RS]

Common Name

English

Ethionamide [WHO-DD]

Common Name

English

ETHIONAMIDE [MART.]

Common Name

English

ETHIONAMIDE [WHO-IP]

Common Name

English

NSC-255115

Code

English

NIZOTIN

Common Name

English

Classification Tree Code System Code

WHO-VATC

QJ04AD03