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At least 19 recordsLinked to original sources
PubMed2003

Reaction and characterization of thioamide dianions derived from N-benzyl thioamides.

Thioamide dianions were generated by the highly efficient reaction of N-benzyl thioamides with 2 equiv of BuLi. Alkylation, allylation, and silylation took place selectively at the carbon atom adjacent to the nitrogen atom of the thioamide dianions. Oxiranes and an aldehyde were also used as electrophiles in the reaction of thioamide dianions to form N-thioacyl 1,3- or 1,2-amino alcohols. The insertion reaction of elemental sulfur to a thioamide dianion and subsequent ethylation afforded a N-thioacyl hemithioaminal. NMR studies on the thioamide mono- and dianions derived from N-benzyl 2-methoxythiobenzamide showed a linear relationship between the chemical shifts of all carbon atoms of thioamide mono- and dianions. The results also suggested that the negative charge at the benzylic carbon atom of the dianion is not fully delocalized. The charge distribution patterns of the dianion are consistent with those of pi polarization.

Journal Article↗
PubMed2001

Compatibility of the thioamide functional group with beta-sheet secondary structure: incorporation of a thioamide linkage into a beta-hairpin peptide.

[structure: see text]. We report the incorporation of a thioamide linkage between the i + 2 and i + 3 residues of the type II' beta-turn of a peptide known to fold into a beta-hairpin conformation. Two-dimensional NMR spectroscopy and circular dichroism spectroscopy indicate that the thioxo peptide adopts a hairpin conformation similar to that of the oxo peptide and that the hairpin conformation persists at elevated temperatures. The results show that a thioamide linkage is compatible with beta-sheet secondary structure.

Circular Dichroism↗
PubMedDate not supplied

Thioamide substrate probes of metal-substrate interactions in carboxypeptidase A catalysis.

Three thioamide peptides in which the oxygen atom of the scissile peptide bond is replaced by sulfur (denoted by (= S)) were synthesized and found to be good, convenient substrates for carboxypeptidase A. The thioamide bond absorbs strongly in the ultraviolet region, and enzymatic hydrolysis is monitored easily using a continuously recording spectrophotometric assay. The reaction follows Michaelis-Menten kinetics with kcat values of 68, 9.0, and 3.7 sec-1 and Km values of 0.83, 0.81, and 0.53 mM for Z-Glu-Phe(= S)-Phe, Z-Gly-Ala(= S)-Phe, and Z-Phe(= S)-Phe, respectively. Activities of the thioamides and their oxygen amide analogs were determined with a series of metal-substituted carboxypeptidases. The Cd(II), Mn(II), Co(II), and Ni(II) enzymes exhibit 30%-35%, 60%-85%, 150%-190%, and 40%-55% of the Zn(II) enzyme activity with the amide substrates; this compares with 240%-970%, 0%-15%, 340%-840%, and 30%-140% of the Zn(II) activity, respectively, with the thioamides. The activity of the Cu(II) and Hg(II) enzymes is less than 3% toward all substrates. Cadmium, a thiophilic metal, yields an enzyme which is exceedingly active with the thioamides; the kcat/Km values are 2.4-9.7-fold higher than with Zn(II) carboxypeptidase. In contrast, Mn(II), which has a relatively low affinity for sulfur, yields an enzyme with correspondingly low activity toward the thioamides. The results are consistent with a mechanism for peptide bond hydrolysis in which the metal atom interacts with the substrate carbonyl atom during catalysis.

Amides↗
PubMed2006

Metabolism of thioamides by Ralstonia pickettii TA.

Information on bacterial thioamide metabolism has focused on transformation of the antituberculosis drug ethionamide and related compounds by Mycobacterium tuberculosis. To study this metabolism more generally, a bacterium that grew using thioacetamide as the sole nitrogen source was isolated via enrichment culture. The bacterium was identified as Ralstonia pickettii and designated strain TA. Cells grown on thioacetamide also transformed other thioamide compounds. Transformation of the thioamides tested was dependent on oxygen. During thioamide degradation, sulfur was detected in the medium at the oxidation level of sulfite, further suggesting an oxygenase mechanism. R. pickettii TA did not grow on thiobenzamide as a nitrogen source, but resting cells converted thiobenzamide to benzamide, with thiobenzamide S-oxide and benzonitrile detected as intermediates. Thioacetamide S-oxide was detected as an intermediate during thioacetamide degradation, but the only accumulating metabolite of thioacetamide was identified as 3,5-dimethyl-1,2,4-thiadiazole, a compound shown to derive from spontaneous reaction of thioacetamide and oxygenated thioacetamide species. This dead-end metabolite accounted for only ca. 12% of the metabolized thioacetamide. Neither acetonitrile nor acetamide was detected during thioacetamide degradation, but R. pickettii grew on both compounds as nitrogen and carbon sources. It is proposed that R. pickettii TA degrades thioamides via a mechanism involving consecutive oxygenations of the thioamide sulfur atom.

Chromatography, High Pressure Liquid↗
PubMed1985

An experimental study of the antileprosy activity of a series of thioamides in the mouse.

A series of substituted thioamides have been studied to establish whether their structure-activity pattern against Mycobacterium leprae is similar to that displayed against M. tuberculosis. Antileprosy activity was evaluated in the mouse foot pad using both the kinetic and continuous methods. Ethionamide and prothionamide were found to be the most active compounds and to be of approximately equal potency. Thioisonicotinamide was about five times less active. 2-t-Butyl-thioisonicotinamide, 2-dimethylamino-thioisonicotinamide, and pyrazine carbonic thioamide were inactive at the dosages tested. High-pressure liquid chromatographic methods were devised to study the potential influence of pharmacological factors on their in vivo activity. Fecal measurements suggested that all of the thioamides were well absorbed when fed in the diet. After intravenous administration, all of the thioamides were rapidly eliminated from the mouse. The differences in their elimination rates probably played only a minor role in affecting their relative antileprosy activities. It was concluded that the structural requirements for antileprosy and antituberculosis activity of the thioamides are probably similar.

Amides↗
PubMed2002

First use of axially chiral thioamides for the stereocontrol of C-C bond formation.

Several N-aryl-substituted thioamides with an axis of chirality along the N-C(aryl) bond were prepared in good to excellent yields. NMR spectra revealed preferences for the E rotamer (along the N-C(=S) bond). X-ray crystallographic analysis showed that the planes of the aryl and thioamide groups were almost perpendicular (79 degrees). For the first time, these atropisomeric thioamides were used for an asymmetric Claisen rearrangement. LDA deprotonation led selectively to the enethiolates of Z stereochemistry, and subsequent reaction with a variety of allyl halides furnished S-allyl keteneaminothioacetals. These intermediates were not detected as they rearranged readily to gamma-unsaturated thioamides in good to high yields and diastereoselectivities up to 88:12. Chemical correlation allowed the assignment of the (aR*,2R*) configuration to the major diastereoisomer. A model was proposed to explain the stereochemical course of the thio-Claisen rearrangement.

Alkylation↗
PubMed1994

Peptidyl thioamides as substrates and inhibitors of papain, and as probes of the kinetic significance of the oxyanion hole.

The interaction of papain with a series of amide and thioamide substrates was studied to assess the contribution of the oxyanion hole to catalysis. Amides 1a-4a (AcPheGly-NHR, where R = H, CH3, PhCH2 or p-O2NC6H4, respectively) were all hydrolyzed to AcPheGly-OH with kcat/Km values from 23-430 M-1s-1 (25 degrees C, 20% v/v MeCN in 50 mM phosphate buffer, pH 6.3). Structurally analogous thioamides 1b-3b (AcPheGlyTNHR) were not detectably hydrolyzed by papain, but 4b (AcPheGlyTNHC6H4NO2) was hydrolyzed to the thiolacid AcPheGly-SH (kcat/Km = 2125 M-1s-1). The latter was hydrolyzed further to AcPheGly-OH in a slower reaction. Thioamides 1b-3b bound to papain and inhibited the papain-catalyzed hydrolysis of Z-Gly-ONp, but the inhibition was generally less than 50% at concentrations up to 500 microM, suggesting that the binding was purely non-covalent. The inability of papain to hydrolyze 1b-3b while 1a-3a are excellent substrates suggests that the oxyanion hole plays an important role in amide hydrolysis by papain. The facile hydrolysis of thioamide 4b was attributed to decreased amide bond resonance (i.e. a more reactive ground state) caused by the strong electron-withdrawing effect of the p-nitrophenyl substituent.

Kinetics↗
PubMed1983

Hepatitis in leprosy patients treated by a daily combination of dapsone, rifampin, and a thioamide.

A 13% incidence of hepatitis was observed among 54 cases of multibacillary leprosy treated daily with the three-drug combination of dapsone, rifampin, and a thioamide (ethionamide or prothionamide). No hepatitis was observed among 109 cases of paucibacillary leprosy treated daily with the two-drug combination of dapsone and rifampin. Symptoms were jaundice in five cases and nausea plus vomiting associated with a significant increase of transaminase levels in two cases. In five cases, the symptoms appeared during the first two months of therapy and in two cases, later. Discontinuing treatment with rifampin and the thioamide but not dapsone resulted in recovery. When rifampin was resumed without the thioamide, the hepatitis did not recur. Viral etiology could be eliminated in six cases. Neither sex, age, weight nor the fact that the patient was a new case or a relapse case appeared to be a contributing factor. Hepatotoxicity caused by administration of a thioamide might have been potentiated by the concurrent administration of rifampin.

Adolescent↗
PubMed2001

Solvent effects on the thioamide rotational barrier: an experimental and theoretical study.

The solvent effect on the C-N rotational barriers of N,N-dimethylthioformamide (DMTF) and N,N-dimethylthioacetamide (DMTA) has been investigated using ab initio theory and NMR spectroscopy. Selective inversion recovery NMR experiments were used to measure rotational barriers in a series of solvents. These data are compared to ab initio results at the G2(MP2) theoretical level. The latter are corrected for large amplitude vibrational motions to give differences in free energy. The calculated gas phase barriers are in very good agreement with the experimental values. Solvation effects were calculated using reaction field theory. This approach has been found to give barriers that are in good agreement with experiment for many aprotic, nonaromatic solvents that do not engage in specific interactions with the solute molecules. The calculated solution-phase barriers for the thioamides using the above solvents are also in good agreement with the observed barriers. The solvent effect on the thioamide rotational barrier is larger than that for the amides because the thioamides have a larger ground-state dipole moment, and there is a larger change in dipole moment with increasing solvent polarity. The transition-state dipole moments for the amides and thioamides are relatively similar. The origin of the C-N rotational barrier and its relation to the concept of amide "resonance" is examined.

Journal Article↗
PubMed2000

Synthesis of N-(Hydroxy)amide- and N-(Hydroxy)thioamide-containing peptides.

Methods developed with N-(benzoyloxy)amines and hydroxamic acids were used in the synthesis of N-(hydroxy)amide-containing pseudopeptides. Acylation of N-(benzoyloxy)phenethylamine with the acid chloride of N(alpha)-Fmoc-L-leucine provided a N(alpha)-Fmoc-N-(benzoyloxy)-L-leucinamide in 90% yield. Deprotection of the benzoyl group (using 10 vol % NH(4)OH/MeOH) provided the N(alpha)-Fmoc-N-(hydroxy)-L-leucinamide in 87% yield. In general, the appended Fmoc group allowed for further elaboration of the N-hydroxy-N-(alkyl)amides using classic peptide-coupling methods. A practical synthetic strategy was developed, and racemization issues were addressed using diastereomeric Val-Leu derivatives. In addition, N-(hydroxy)thioamides were generated from the corresponding N-(benzoyloxy)thioamides. N-(Benzoyloxy)thioamides were obtained in moderate yields (53-76%) from the reaction of the corresponding N-(benzoyloxy)amides with Lawesson's reagent (i.e., 2, 4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disu lfide). In summary, this new technology allows for the introduction of either N-hydroxyamide or N-(hydroxy)thioamide linkages into pseudopeptide chains without racemization.

Acylation↗
PubMed2004

Computational study of conformational preferences of thioamide-containing azaglycine peptides.

The effect of thioamide substitution on the conformational stability of an azaglycine-containing peptide, For-AzaGly-NH2 (1), was investigated for the sake of finding possible applications by using ab initio and DFT methods. As model compounds, For-[psiCSNH]-AzaGly-NH2 (2), For-AzaGly-[psiCSNH]-NH2 (3), and For-[psiCSNH]-AzaGly-[psiCSNH]-NH2 (4) were used. Two-dimensional phi-psi potential energy surfaces (PESs) for 2-4 were calculated at the B3LYP/6-31G*//HF/6-31G* level in gas (epsilon = 1.0) and in water (epsilon = 78.4) by applying the isodensity polarizable continuum model (IPCM) method. On the basis of these PESs, the minimum energy conformations for 2-4 were characterized at the B3LYP level with 6-31G*, 6-311G**, and 6-31+G** basis sets. The remarkable structural effect of thioamide substitution for 2-4 is that beta-strand structure is observed as a global or local minimum. The minima of 2-4 are also compared with those for glycine and thioamide-containing glycine peptides. Our theoretical results demonstrate that compounds 2-4 would be used to design controllable secondary structures.

Glycine↗
PubMedDate not supplied

Preparation of thioamide building blocks via microwave-promoted three-component kindler reactions.

A microwave-enhanced variation of the Kindler thioamide synthesis is introduced. Taking advantage of the sealed vessel capabilities of a dedicated single-mode microwave reacto,r a diverse selection of 13 aldehyde and 12 amine precursors was utilized in the construction of a representative 34-member library of substituted thioamides. The three-component condensations of aldehydes, amines, and elemental sulfur were carried out using 1-methyl-2-pyrrolidone (NMP) as solvent employing microwave flash heating at 110-180 degrees C for 2-20 min. A simple workup protocol allows the isolation of synthetically valuable primary, secondary, and tertiary thioamide building blocks in 83% average yield and >90% purity.

Benzaldehydes↗
PubMed1991

The effect of methimazole on thioamide bioactivation and toxicity.

The hepatotoxicity induced by administration of ethionamide and thionicotinamide (TNA) was shown to be decreased by pre-administration of methimazole (MMI). Pre-administration of MMI was also shown to decrease the levels of excretion of TNA S-oxide. This indicates that thioamide S-oxidation, mediated by the flavin-containing mono-oxygenase, may be linked to the initiation of hepatotoxicity induced by these thioamides. SK&F-525-A, the cytochrome P-450 inhibitor, did not affect either thioamide-induced toxicity or levels of excretion of TNA S-oxide; however, the role of the P-450 isoenzymes cannot be totally ruled out.

Animals↗