[Study of thioamides and their derivatives. I. Reactions of thioamides and quaternary salts of N,N-disubstituted thioamides with N3-substituted amidrazones].
Explore the source record for details and available documents.
Amides↗
SEARCH · Search PubMed
Results for “Thioamides”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Studies on thioamides. 3. A new synthetic method of the 3,4-dihydroisoquinoline derivatives by the cyclodesulfurization of thioamides.
Explore the source record for details and available documents.
Amides↗
[Reinforcement in vitro of the antibacillary action of ethionamide (2-ethyl isonicotinic acid thioamide, 1314 Th) and of prothionamide (alpha-propyl-isonicotinic acid thioamide, 1321 Th) by sodium pyruvate].
Explore the source record for details and available documents.
Amides↗
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↗
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↗
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↗
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↗
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↗
Evidence of a peptide backbone contribution toward selective receptor recognition for leucine enkephalin thioamide analogs.
The in vitro opioid activities of a series of leucine enkephalin analogs containing a thioamide linkage in place of the peptide bond at various positions of the backbone were determined in mu- and delta-receptor-selective bio- and binding-assays. Thioamide substitution in the 1-2 position resulted in an inactive compound, whereas the same modification in the 2-3 and 4-5 position produced potency enhancement. Most interestingly, the 2-3 modified analog showed a 3 to 5 times higher preference for delta- over mu-receptors than natural leucine enkephalin. These results suggest that subtle backbone modifications can have a profound effect on receptor affinity and selectivity of biologically active peptides.
Amides↗
Biological activities of cyclic enkephalin pseudopeptides containing thioamides as amide bond replacements.
Analogs of H-Tyr-cyclo(N epsilon-D-Lys-Gly-Phe-Leu) have been prepared which contain thioamides at the 3-4 position (monothio), 3-4 and 5-2 positions (dithio), and 2-3, 3-4, and 5-2 positions (trithio). These compounds have been tested for opioid activity in mu- and delta-receptor selective bio- and binding assays. As the number of sulfurs increased, the biological activities dropped on the guinea pig ileum and fluctuated modestly on the mouse vas deferens assay. Surprisingly, the compounds displayed increasing delta selectivity as the number of sulfurs increased. In the binding assay, the thioamide analogs tended to retain affinity toward the mu receptor. The mono- and dithio-analogs were more mu selective than the parent, while the trithio-analog was more delta selective. These results suggest that the subtle exchange of sulfur for oxygen can have a significant impact on receptor selectivity and affinity, and probably reflect the different conformation/structural requirements for binding vs. the biological transduction event.
Amides↗
5,6,7,8-Tetrahydroguinolines. 4. Antiulcer and antisecretory activity of 5,6,7,8-tetrahydroquinolinenitriles and -thioamides.
A number of 5,6,7,8-tetrahydroquinoling-8-nitriles and -8-thioamides and related compounds have been found to be potent inhibitors of basal gastric secretion in the pylorus-ligated rat and to afford protection against gastric erosions induced in rats by cold-restraint stress. Molecular manipulation has proved useful in determining factors necessary for such activity and structure-activity relationships are discussed. It has been shown that the most necessary requirements for activity are a pyridine nitrogen with its available lone pair and a primary or secondary thioamide. Also desirable is a six-membered carbocyclic ring with relative freedom from steric hinderance around the 8 position.
Animals↗
Intramolecular H-bonds and thioamide rotational isomerism in thiopeptides.
Mono- and dithionated N-acyl amino acid and dipeptide N'-methylamides were synthesized using Lawesson's reagent and S-thioacetyl thioglycolic acid. The conformation of the thionated models was characterized by IR, 13C, and 1H NMR spectroscopy, including NOE experiments. The formation of -C = S...H-N-C = X (X = O or S) intramolecular H-bonds of the type 2----2, 1----3 and 1----4 was evidenced by the characteristic shifts of the IR stretching frequencies of the NH group. Act-Pro-NHCH3(4) and Act-Prot-NHCH3(5) were found to be present as mixtures of rotational isomers about the CS-N bond. 13C chemical shifts of the gamma- and beta-carbons of the proline ring elucidated the conformation (Z or E) of the tertiary thioamide group. Our results suggest that the conformation of thiopeptides is determined by two factors: 1) the H-bond donating and accepting ability of the thioamide group and 2) the repulsion between the thiocarbonyl sulfur atom and the side chain groups of the neighbouring amino acid residues.
Dipeptides↗
Mechanism of thioamide antithyroid drug associated hypoprothrombinemia.
The thioamide class of antithyroid drugs has been associated with the development of hypoprothrombinemia. Two drugs in this class, propylthiouracil and methimazole, resemble the methyltetrazole-thiol leaving group of certain cephalosporin antibiotics. Both were found in vitro to inhibit the vitamin K dependent step in clotting factor synthesis, the gamma-carboxylation of glutamic acid with 50 per cent inhibitory concentrations of 2 mM for propylthiouracil and 0.1 mM for methimazole. Methimazole was also found to inhibit vitamin K epoxide reductase, an enzyme related to the carboxylation reaction, with a 50 per cent inhibitory concentration of 25 uM. In vivo methimazole, administered twice at a dose of 500 mg/kg to rats on a vitamin K deficient diet produced hypoprothrombinemia. These results suggest that the mechanism of hypoprothrombinemia associated with thioamide antithyroid drugs may be similar to the mechanism of hypoprothrombinemia associated with cephalosporins which contain the methyltetrazole-thiol leaving group.
Amides↗
Synthesis and some biological properties of the hexapeptide analog of substance P with a C-terminal thioamide group.
A new hexapeptide analog of Substance P, containing a C-terminal thioamide group in the molecule [( Glp6, Mett11]SP6-11) was synthesized: Glp-Phe-Phe-Gly-Leu-Mett-NH2. Conversion to thioamide was accomplished from tert-butoxycarbonyl-L-methionine amide (Boc-Met-NH2) using Lawesson's Reagent. Its contracting activity on isolated guinea-pig ileum was considerably lower than that of [Glp6]SP6-11.
Animals↗
Kinetics and mechanisms of thioamide rotational isomerism: N-thionaphthoyl-N-methyl glycine derivative.
Thioamide, 1, is shown to exist as two rotameric forms in solution, rotamer A and B. Conformations of the rotamers are defined to be trans for rotamer A and cis for rotamer B. Energy barriers restricting rotation about the C--N bond of the thioamide group are examined as a function of pH, temperature, buffer concentration, ionic strength, and dielectric constant. Kinetic parameters, kobs, k1, k2, Ea, delta S not equal to, delta H not equal to, and Keq are obtained. No significant buffer effect is observed. Ionic strength (0.2-0.8) does not markedly affect the rate of interconversion. The extent of reaction (Keq) is related to dissociation of the carboxylic acid function. The reaction rate decreases with increasing polarity of solvent which retards interconversion. The energy barriers (Ea = 25-26 kcal/mol) are almost invariant with changing pH values. When protected from light, rotamer A is thermodynamically more stable than rotamer B. The rotamer ratio is dependent on pH and temperature. Under 500 foot-candle light exposure, the ratio of rotamer A to B is close to one at 30 degrees C.
Buffers↗
TRH analogue with C-terminal thioamide group: rapid degradation by plasma and its biological effects.
L-pyroglutamyl-L-histidyl-L-proline thioamide--([Prot3]TRH), a new TRH analogue, has been previously found to have the same binding affinity to adenopituitary receptors as well as TSH and alpha-MSH releasing activities as native TRH. In this paper we report also the same time course of TSH response after i.p. injection of this compound (10 micrograms kg-1) to rats. Binding affinity to specific receptors in rat amygdala, cortex (frontal lobes), hypothalamus, striatum (order according to decreasing affinity) of both peptides was also similar. In contrast to TRH, however, [Prot3]TRH in doses 0.5 and 5 mg kg-1 i.p. did not affect sleeping time and breathing frequency in the rats during barbiturate anaesthesia. Surprisingly, human plasma degraded the new analogue much faster (T1/2 8.5 min) than native TRH (T1/2 30 min). [Prot3]TRH was also degraded faster in plasma of adult rats. Plasma of 6-day-old rat pups failed to degrade both peptides. It was concluded that the substitution of proline amide, for proline thioamide group in TRH molecule did not change binding affinity to receptors in the central nervous system, but decreased biological effectiveness in CNS and substantially decreased the resistance to degradation in human and rat plasma.
Animals↗
[Azoles. 12. Pyrazole carbolic acid thioamides].
Morpholids, N-methylpiperazids, piperidids and pyrrolidids of 5-methyl, 3,5-dimethyl-1-phenyl-4-pyrazolthioacetic acid and 3,5-dimethyl-1-phenyl-4-pyrazolcarbonic acid 4-12 are obtained by the Willgerodt-Kindler procedure. The oxothioamids 13-19 result as the intermediate products of the synthesis of thioamids 4-10. The compounds 4, 5, 8, 9, 11, 14 and 17 do not respond to Mycobacterium tuberculosis H37Rv. The thioamids 4, 8 and 11 are of slight toxicity (LD50 greater than 2.8 g/kg, albino-Swiss mice) and inhibit the Carrageenin oedema of the Wistar rat claw minor than phyenylbutazon and indometacin.
Animals↗
Familial thioamide-induced lupus syndrome in thyrotoxicosis.
We describe 2 relatives both with thyrotoxicosis who developed a lupus-like syndrome after treatment with thioamide derivatives, methimazole (father) and propylthiouracil (son). The lupus syndrome consisted of joint pains, skin rash, and positive antinuclear antibodies (son), all of which resolved after discontinuation of the antithyroid medications. Both patients were identical at the HLA-DR locus suggesting adverse reactions to thioamides may be controlled by immune response genes. The clinician should be cautious about treating other family members when 1 member has had a drug-induced lupus syndrome. This is especially true if the disease in question is a known familial illness such as thyrotoxicosis.
Adolescent↗