Ethionamide

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Cat Number

API0232293

CAS Number

536-33-4

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CAS Number

536-33-4

EINECS

208-628-9

Storage

Store at room temperature

Synonyms

2-ethylpyridine-4-carbothioamide; Trecator; Ethioniamide; Amidazine; Ethyonomide; Etionamid; Etioniamid; 2-Ethylthioisonicotinamide

Molecular Formula

C8H10N2S

Molecular Weight

166.25

Smiles

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

Appearance

Yellow crystalline powder

Melting Point

164°C

Relative Density

1.1332 (Estimate)

General Description

Ethionamide is a synthetic derivative of isonicotinic acid with a thioamide group, belonging to the class of second-line antituberculosis agents. Its chemical structure is 2-ethylpyridine-4-carbothioamide. Ethionamide is a yellow crystalline powder, practically insoluble in water but soluble in organic solvents. The molecule is structurally related to isoniazid but with a different mechanism of action.

Mechanism of Action

Ethionamide is a prodrug that is activated by the bacterial enzyme EthA, a monooxygenase, which converts it to the active metabolite. The active metabolite inhibits the synthesis of mycolic acid, a key component of the mycobacterial cell wall, by blocking the enzyme InhA. This leads to the disruption of the cell wall and the death of the bacteria. The drug is bactericidal against Mycobacterium tuberculosis.

Application

Ethionamide is indicated for the treatment of multidrug-resistant tuberculosis (MDR-TB), in combination with other antituberculosis agents. It is used in patients who are resistant to first-line agents, such as isoniazid and rifampin. The drug is effective in reducing the bacterial load and improving treatment outcomes, but it is associated with significant gastrointestinal side effects.

Deletion of the ethA/R locus in Mycobacterium bovis BCG conferred complete ethionamide resistance, but in Mycobacterium tuberculosis, ethA/R knockout mutants retained partial susceptibility, indicating an alternative bio-activation pathway. Reintroduction of ethR did not restore resistance. Spontaneous resistant mutants from ethA/R KO MTB identified mshA mutations. Deletion of mshA in ethA/R KO MTB led to complete resistance, and mshA single KO MTB showed resistance comparable to ethA/R KO. MshA is as critical as ethA/R for ethionamide killing in MTB.

Fig. 1 <i>In vitro</i> growth kinetics of mshA KO and mshA ethA/R (m/e) double KO mutants. (Ang MLT, <i>et al</i>., 2017) Fig. 1 In vitro growth kinetics of mshA KO and mshA ethA/R (m/e) double KO mutants. (Ang MLT, et al., 2017)

References

Ang MLT, et al. EthA/R-Independent Killing of Mycobacterium tuberculosis by Ethionamide. Front Microbiol. 2017;8:710.

Comparative transcriptomics of extensively drug‑resistant M. tuberculosis identified a promoter mutation (t‑11c) in ethA that reduced EthA expression, conferring ethionamide resistance independently of EthR. This mutation can cause high‑level resistance when combined with other mutations. Global transcriptional changes, including toxin‑antitoxin modules and tRNAs, were also observed in XDR strains, suggesting broader adaptive mechanisms.

Fig. 2 Analysis of promoter activity between the wild-type (WT) and mutant (MUT) constructs. (de Welzen L, et al., 2017)

References

de Welzen L, et al. Whole-Transcriptome and -Genome Analysis of Extensively Drug-Resistant Mycobacterium tuberculosis Clinical Isolates Identifies Downregulation of ethA as a Mechanism of Ethionamide Resistance. Antimicrob Agents Chemother. 2017;61(12):e01461-17.

Does Ethionamide require protection from light and moisture during storage?

Yes, it is sensitive to both light and moisture. Light causes photodegradation and moisture promotes hydrolysis of the thioamide group. Store in light‑resistant, tightly sealed containers with desiccant.

What is the recommended storage temperature for Ethionamide?

Store at controlled room temperature (15–25°C). Avoid excessive heat above 30°C, which accelerates degradation and discoloration.

Is Ethionamide stable in tablet formulations with standard excipients?

Yes, when formulated with moisture‑protective packaging.

How is the impurity ethionamide sulfoxide (an oxidative degradation product) monitored?

This degradation product is specifically quantified using a stability‑indicating HPLC method, ensuring it remains within pharmacopoeial limits.