Disease relevance of ethionamide

• Thioamide drugs, ethionamide (ETH) and prothionamide (PTH), are clinically effective in the treatment of Mycobacterium tuberculosis, M. leprae, and M. avium complex infections [1].
• Production of EtaA appears to be negatively regulated by EtaR and correlates directly with [(14)C]ETA metabolism, suggesting that EtaA is the activating enzyme responsible for thioamide oxidation and subsequent toxicity [2].
• Evaluation of compounds 6, 7a, 7b, 7c, 9a, 9b, 9c, 11 for cytoxicity and activity against human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1) revealed that only the carboxamide (7a) and the thioamide (7c) were active [3].
• Evaluation of compounds 4 and 6-12 for activity against human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1) revealed that only the thioamide (11) was active [4].
• Synthesis of thioamide bond catalyzed by E. coli ribosomes [5].

High impact information on ethionamide

• EtaA is a newly identified FAD-containing monooxygenase that is responsible for activation of several thioamide prodrugs in Mycobacterium tuberculosis [6].
• A flexible alignment of the most potent compounds of the thioamide and thiourea class and a QC substrate revealed a good match of characteristic features of the molecules, which suggests a similar binding mode of both inhibitors and the substrate to the active site of QC [7].
• Comparisons show that, while NADP+ and NADPH bind to DHFR with the pyridine ring and 3'-carboxamide coplanar, the thioamide group is twisted by 23 degrees from the pyridine plane in both the binary and ternary complexes [8].
• The effects of changes in pyridyl group, thioamide, and thiane ring on in vitro K(+)-channel opening reactivity are discussed [9].
• A series of aldose reductase inhibitors was prepared in which structural modifications were made to three positions of the potent, orally active inhibitor tolrestat (1), namely, the 6-methoxy substituent, thioamide sulfur, and the N-methyl moiety [10].

Chemical compound and disease context of ethionamide

• The effect of methimazole on thioamide bioactivation and toxicity [11].
• During amiodarone therapy, the clinical features of thyrotoxicosis may be masked or atypical, and the choice of therapy is complicated by a delayed response to thioamide drugs and possible contraindication for beta-blocking agents which necessitates the use of glucocorticoid drugs in some patients [12].

Biological context of ethionamide

• Alkylation, allylation, and silylation took place selectively at the carbon atom adjacent to the nitrogen atom of the thioamide dianions [13].
• Thioamide therapy has improved the outcome of pregnancies complicated by maternal hyperthyroidism, without long-term effects on cognitive and somatic development [14].
• Synthesis and QSAR studies of novel triazole compounds containing thioamide as potential antifungal agents [15].
• From molecular free energy calculations, it is shown that the main influence of the introduction of a thioamide bond on the molecular structure is to prevent the existence of C7(eq) conformations involving the thiomethionine residue [16].
• Although single amino acid substitutions (e.g. Aib) can restrict the available conformations, they do not necessarily lead to unique conformers, however, we predict that some of the amino acids described in this report will fold to a single phi, psi conformation (e.g. N-methylated and thioamide penicillamine) [17].

Anatomical context of ethionamide

• Our review also indicates that impairment of neonatal thyroid function may be minimized by using a thioamide dose that is just sufficient to maintain the maternal serum free thyroxine concentration in the high normal or slightly thyrotoxic range [14].

Associations of ethionamide with other chemical compounds

• A thioamide analogue of bestatin (49) is a modest inhibitor of AP-M (Ki = 40 microM), LAP (Ki = 0.33 microM), and AP-B (Ki = 2.4 microM) [18].
• The thioamide derivative showed highly Hg2+-selective fluorescence enhancing properties (167-fold) in 30% aqueous acetonitrile solution [19].
• A target of the anti-tuberculosis drugs isoniazid (INH) and ethionamide (ETH) has been shown to be an enoyl reductase, encoded by the inhA gene [20].
• The native microsome-bound flavin-containing monooxygenase of mouse, rabbit, and rat liver, lung, and kidney can metabolize compounds containing thiol, sulfide, thioamide, secondary and tertiary amine, hydrazine, and phosphine substituents [21].
• The compounds, diversely substituted on the phenyl ring by alcohol, nitrile, ether, ketone, amide and thioamide groups, were tested for their ability to inhibit epidermal growth factor (EGF) receptor-associated tyrosine kinase activity in vitro [22].

Gene context of ethionamide

• Carbobenzoxythioglycyl-L-phenylalanine [CbzNHCH2C(==S)Phe, Z-Glys-Phe] was synthesized as thioamide analogue of Z-Gly-Phe, a known substrate of carboxypeptidase A (CPA) [23].
• Solid phase synthesis of a GHRP analog containing C-terminal thioamide group [24].
• Axially chiral thioamide ligands L5, L6, L8, L11, and bis(thioamide) ligand L13 were prepared from the reaction of (S)-(-)-1,1'-binaphthyl-2,2'-diamine with acyl chlorides and phosphorus pentasulfide (P2S5) [25].
• Thioamide substrate probes of metal-substrate interactions in carboxypeptidase A catalysis [26].
• TRH analogue with C-terminal thioamide group: rapid degradation by plasma and its biological effects [27].

Analytical, diagnostic and therapeutic context of ethionamide

• Conversion of the thioamide to the nitrile was caused by components in the cell culture medium, not components of serum [28].
• Minimum inhibitory concentrations fall into a range of 32->1000 micromol/l. The most active substances bear two nitro groups or a thioamide group on the benzyl moiety [29].
• The thioisomünchnone 18, derived from diazo thioamide 17, is an extremely stable crystalline mesoionic system which can be characterised by X-ray crystallography but fails to undergo intramolecular cycloaddition [30].
• It was found that this biosensor is especially sensitive to seven chemicals that have a thiocarbonyl functional group (>C=S), such as a thioamide group of thiocarbamate group [31].
• A simple high-performance liquid chromatography method has been developed that allows the sensitive determination of protionamide (2-n-propyl-pyridine-4-carboxylic acid thioamide, PTH) in human serum [32].

References