Methylthio Derivatives Research Articles

Azoles. Part 9. Synthesis of derivatives of thieno[2,3-d]thiazole, 4H-pyrrolo-[2,3-d]thiazole, 2H-pyrazolo[3,4-d]thiazole and isoxazolo[3,4-d]thiazole from thiazolidine-2,4-dione

The aldehyde group of 2,4-dichlorothiazole-5-carbaldehyde was protected and the chlorine atom at position 2 was replaced by hydrogen and a methylthio group, via Cl → Li exchange, to give 4-chloro-thiazole-5-carbaldehyde and its 2-methylthio derivative, respectively. Ethyl 2-mercaptoacetate reacted with 4-chlorothiazole-5-carbaldehydes to give thieno[2,3-d]thiazoles. Saponification of ethyl thieno[2,3-d]thiazole-5-carboxylate and attempted decarboxylation of the resulting acid failed to yield enough of the parent thieno[2,3-d]thiazole to allow full characterisation owing to its high volatility.4-Azidothiazole-5-carbaldehydes were prepared by nucleophilic displacement of the chlorine atom in the corresponding 4-chlorothiazole-5-carbaldehyde and converted into alkenes and Schiff's bases by standard procedures. On being heated in toluene these afforded the corresponding 4H-pyrrolo-[2,3-d]thiazole or 2H-pyrazolo[3,4-d]thiazole. lsoxazolo[3,4-d]thiazole and its 2-methylthio derivative, both unstable, were obtained by heating the corresponding 4-azidothiazole-5-carbaldehyde in bromobenzene.

Amino acids in the synthesis of heterocyclic compounds. Transformations of thiazolones into imidazole derivatives

5(4H)-Thiazolone derivative 4, obtained from N-dithiocarbobenzoxyglycine (1) and N,N-dimethyl-N′-heteroarylformamidines 3 in acetic anhydride, was rearranged with sodium methoxide in methanol followed by acidification with acetic acid into imidazole-4-carboxylic acid derivatives 5, 6 and 7. These were further converted with methyl iodide into methylthio derivatives 8, with hydrogen peroxide into the corresponding disulphide 9, with hydrazine and amines into hydrazide 10 and amides 11. In the reactions of 4a and 6a with amines in the presence of dichloromethane symetrically disubstituted methanes 14–18 were formed.

Carbapenem and penem antibiotics. IV. Carbapenem and penem antibiotics. V.Synthesis and antibacterial activity of 2-functionalized-methyl 1-methylcarbapenems related to asparenomycins.

The synthesis of 1 alpha- and/or 1 beta-methylcarbapenems, 2-unsubstituted and 2-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl derivatives having a 1-(hydroxy)methylethylidene or cyclic carbonate side chain at the C-6 position, is described. The in vitro antibacterial activities of these compounds and their corresponding 1-unsubstituted carbapenems are compared.

The preparation and reactions of 2‐halogenoethyl β‐L‐arabinopyranosides

AbstractAcid‐catalysed reaction of L‐arabinose with 2‐chloroethanol, 2‐bromoethanol or 2‐iodoethanol at 50‐60 °C, afforded the highly crystalline 2‐haloethyl β‐L‐arabinopyranosides in 20%, 86% and 23% yields respectively, which each crystallised out directly from the reaction mixtures. Following O‐acetylation of 2‐bromoethyl β‐L‐arabinopyranoside, the bromo substituent underwent substitution by various nucleophilic anions (N3−, NCS−, AcS−, BzO−) to give the appropriate acetylated functionalised glycosides. O,S‐Deacetylation of 2‐(acetylthio)ethyl 2,3,4‐tri‐O‐acetyl‐β‐L‐arabinoside afforded 2‐mercaptoethyl β‐L‐arabinopyranoside, but deblocking of the 2‐thiocyanatoethyl 2,3,4‐tri‐O‐acetyl‐P‐L‐arabinoside in the same way afforded the thiol as a minor product, with the derived disulphide and methylthio derivatives as the major products. The origin of these compounds is discussed. Reaction of the 2‐bromoethyl arabinoside with base afforded the as‐fused bicycle 1,2‐O‐ethylene‐β‐L‐arabinopyranose in high yield. Acetonation and subsequent oxidation of the 2‐azidoethyl arabinoside gave the 2‐ketone, reductive amination of which led to the trans‐fused bicycle 2‐amino‐2‐deoxy‐1,2‐O, N‐ethylene‐β‐L‐ribose. Chlorination of 2‐chloroethyl β‐L‐arabinopyranoside with triphenylphosphine/carbon‐tetrachloride, followed by treatment with base afforded 3,4‐anhydro‐1,2‐O‐ethylene‐β‐L‐arabinopyranoside, ring‐opening of which by azide proceeded regiospecifically to give the 4‐azido‐D‐xylo isomer, which was reduced to the amine.

ChemInform Abstract: Synthesis and Mass Spectra of 2,3‐Dihydro‐1H‐1,5‐benzodiazepine‐2‐thiones.

AbstractTreatment of the 1,5‐benzodiazepinones (I) with phosphorus pentasulfide gives the corresponding thiones (II) of which (IIa) and (IIb) are methylated, producing the methylthio derivatives (IVa) and (IVb).

Synthesis of sweet-tasting methylthio derivatives of d-fructose and sucrose

1,6-Di- S-methyl-1,6-dithio- d-fructofuranose and its bis( S-oxide) and bis( S,S-dioxide) are described. On examination for sweetness, the oxygenated compounds were neutral but the parent compound was 15–20 times sweeter than sucrose, and 1′,6′-di- S-methyl-1′,6′-dithiosucrose was slightly less sweet than sucrose.

α‐Cyanothioacetamide and its derivatives in heterocyclic synthesis: Preparation of several new 4‐oxoquinazoline derivatives

AbstractThe reaction of α‐cyanothioacetamide (1) or its methylthio derivative (2) with anthranilic acid led to the formation of 3,4‐dihydro‐4‐oxoquinazolin‐2‐yl acetonitrile (3). 3 condensed with aromatic aldehydes to give arylidene derivatives (4a‐d) which could be prepared also via the reaction of 2‐thiocarbamoylcinnamonitriles (5a‐d) or their methylthio derivatives (6a‐d) with anthranilic acid. 3 reacted with cinnamonitrile derivatives (7a‐h) and (12a‐d) to yield pyrido‐[1,2‐a]‐quinazoline derivatives (10a‐h) and (15a‐d) which could also be prepared by the reaction of (4a‐d) with malononitrile (11a), benzoyl acetonitrile (11b) and ethylcyanoacetate (16), respectively.

New multi-stage redox systems and new organic molecular metals

Abstract

Reaktionen von Dithiocarbonsäureestern mit CH-acidem Isothiocyanatoessigester - Eine neue Synthese von 2-Methylthio-1,3-thiazolen

Methyl arylcarbodithioates react with ethyl isothiocyanatoacetate in the presence of sodium hydride in tetrahydrofuran to give the sodium salts of ethyl 5-aryl-2-mercapto-1,3-thiazole-4-carboxylates. In situ methylation affords the corresponding 2-methylthio derivatives

Pharmacokinetics and metabolism of oral doses of a 4′-methylthio derivative of propranolol in man

1. The objective of this study was to determine the oral dose pharmacokinetics and metabolism of 4'-methylthiopropranolol (MTP) in man and compare the results with observations for propranolol in previous studies. 2. Three women and five men received single oral doses of MTP, dose range 5-320 mg. Plasma concentration of MTP over time were measured by gas chromatography-mass spectrometry. MTP metabolites in urine were identified by comparative high-performance liquid chromatographic (HPLC) retention times and mass spectrometry with previously characterized reference compounds and quantified by HPLC. 3. The oral clearance of MTP of 1.2-1.4 l/min for the 80, 160 and 320 mg doses was about one third of the value previously reported for propranolol. The half-life for MTP (3.3-4.1 h) was, however, similar to that of propranolol. In contrast to propranolol, the peak (2.5 h) plasma concentrations of MTP increased linearly with dose (5-320 mg). 4. The oral clearance for MTP was about 2-fold higher in the men than in the women (P less than 0.01). In addition, the clearance of the (S)-enantiomer was about 30% higher than that of the (R)-enantiomer (P less than 0.05), which was a reversal of that seen with propranolol. 5. The metabolism of MTP resulted mainly in sulphur oxidation to sulphoxide and sulphone metabolites. These two metabolites accounted for 75% of the MTP dose. This switching from aromatic carbon oxidation for propranolol to sulphur oxidation for MTP is proposed as the basis of the lower oral clearance of MTP. 6. This study also demonstrated higher plasma binding of MTP (unbound fraction 3.7%) than of propranolol (10.5%; P less than 0.01), a factor probably contributing to decreased tissue distribution of MTP.

Alkylation and reductive dethionation of 2-thioxo- and 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid derivatives

2-Methylthio-1,4-dihydropyrimidines were obtained by methylation of 2-thioxo-4-phenyl-5-methoxycarbonyl-6-methyl-1,2,3,4-tetrahydropyrimidine or its 1-methyl derivative in a neutral medium. The alkylation of tetrahydropyrimidine-2-thiones in the anionic form leads to S- and S,N-methylation products. Iodoacetamide alkylates pyrimidine-2-thione with the formation of thiazolidino[3,2-a]pyrimidine derivatives. The reductive dethionation of derivatives of tetrahydropyrimidine-2-thiones and 2-methylthio derivatives of 1,4- and 3,4-dihydropyrimidines was accomplished.

Molecular cloning of the Escherichia coli miaA gene involved in the formation of delta 2-isopentenyl adenosine in tRNA.

Escherichia coli mia strains were shown to lack delta 2-isopentenylpyrophosphate transferase activity, the first step in the synthesis of the 2-methylthio derivative of 6-(delta 2-isopentenyl) adenosine (ms2i6A). A double mutant, rpsL (Smp) miaA, was streptomycin dependent. The wild-type miaA gene was cloned by selecting for lambda recombinant bacteriophage which eliminated the streptomycin-dependent phenotype and was subsequently recloned into plasmid vectors. The cloned miaA gene restored the ms2i6A modification to tRNA. The miaA gene mapped to 95 min on the E. coli map, and we propose the order mutL-miaA-hflA-purA.

ChemInform Abstract: Synthesis of Bridgehead‐Nitrogen Heterocycles from Pyrylium Salts: Preparation of the Novel Tricyclic Thiazolo(2,3‐c)pyrido(2,1‐f)(1,2,4)triazine Ring System.

AbstractCyclization of the ethoxycarbonyldiphenylpyrylium tetrafluoroborate (I) with the thiosemicarbazide (II) produces the dihydropyridotriaziniumthiolate (III) which is alkylated with the phenacyl bromides (IV) and trimethyloxonium tetrafluoroborate (VII), forming the phenacylthio or methylthio derivatives (V) and (VIII) respectively.

Glutathione transferase from Mucor javanicus.

Glutathione transferase was purified from Mucor javanicus and characterized as a dimer of identical subunits (Mr; 22, 000). Kinetics and Km values of M. javanicus glutathione transferase, 0.48 mM and 1.0 mM (at pH 6.5) for glutathione and 1-chloro-2, 4-dinitrobenzene, are close to those of rat liver enzyme, but occurrence of isoenzymes was not recognized in M. javanicus. The best substrate of M. javanicus glutathione transferase was 1-chloro-2, 4-dinitrobenzene. On the other hand, 2, 3-, 2, 4-, 2, 5-, and 3, 4-dichloronitrobenzenes were converted to the related conjugates by 0.17 to 0.35% of the velocity toward the best substrate. This is correlated to the previous result that 2, 3-and 2, 4-dichloronitrobenzenes were metabolized to 2-methylthio derivatives by the incubation with M. javanicus.

Characterization of seawater samples using chemometric methods applied to biomarker fatty acids

Dissolved and particulate fatty acids have been analyzed by gas chromatography and gas chromatography/mass spectrometry in microlayer and subsurface water samples from the open Mediterranean sea. Structural elucidation of these compounds was performed before and after derivatization with dimethyldisulfide (DMDS) by GC/MS analyses of the fatty acid methyl esters (FAMEs) and their methylthio derivatives to locate the double bond of the monounsaturated FAMEs. Several hundred data were analyzed using a statistical approach. A multivariate method, CFA (Correspondence Factorial Analysis), and a non-parametric procedure. HCC (Hierarchical Clustering Classification), were used together to investigate the planktonic and microbiological sources in order to further characterize our samples. These statistical treatments allowed us to distinguish different inputs in the dissolved and particulate material: esters in the particulate material showed a major phytoplanktonic input dominated by the presence of diatoms except in one sample where zooplankton prevailed. Higher amounts of C 15 and C 17 branched and monounsaturated FAMEs indicated a stronger bacterial fingerprint for the dissolved FAMEs. C 16:1 ω10 , previously unreported in seawater displayed a similar statistical behavior as other bacterial FAMEs suggesting a microbial origin of this compound. Dissolved FAMEs extracted from acidified seawater and particulate esterified FAMEs showed similar composition.

Mechanisms of fasting-induced potentiation of acetaminophen hepatotoxicity in the rat

The effects of an acute fast on acetaminophen metabolism and hepatotoxicity were investigated in male Long Evans Hooded rats. Histologic studies confirmed that fasting potentiated acetaminophen-induced hepatic necrosis. The previous known fasting-induced decrease in hepatic levels of glutathione and depletion of glycogen levels were also confirmed. Pharmacokinetic studies revealed that, at high dose levels of acetaminophen, fasting decreased the overall rate of elimination as evidence by a longer blood half-life of the drug. The decreased clearance was largely the result of decreases in the apparent rate constants for glucuronidation ( ca. 40%) and for sulfation ( ca. 30%). Fasting had no significant effects on the apparent rate constants for formation of either acetaminophen mercapturate or the methylthio derivatives. The depression of the nontoxic glucuronidation and sulfation pathways resulted in an increased proportion of the dose converted to the toxic metabolite and, hence, contributed to the potentiation of liver injury in fasted rats. In addition, these studies demonstrated that significant glucuronidation capacity ( ca. 60% of that in fed rats) was maintained in fasted rats, indicating that: (a) the glucuronidation capacity was not directly correlated with glycogen levels; and (b) in fasted rats the glucose required for UDP-glucuronic acid formation for acetaminophen glucuronidation was supplied from sources other than glycogen.

Rh(III), Pd(II), Pt(IV) und Au(III) Komplexe von 2-Thiopyrimidin Derivaten

Some news thiopyrimidine derivatives and complexes [4-amino-5-nitroso-6-oxo-1,2,3,6-tetrahydro-2-thio-pyrimidine (TANH), its 2-methylthio derivative (MTH), the ammonium salt ofTANH (sTANH) and six new complexes of formulas: Rh(MT)2Cl · 2H2O, Pd(MTH)2Cl2, Pt(MTH)2Cl4, Au(MTH)Cl3 Pd(TANH)2Cl2 and Au(TAN−)Cl] have been synthesized and characterized by elemental analysis, IR and1H-NMR spectroscopy techniques. The thermal behaviour of all compounds has also been studied.

Excretion, distribution and metabolism of 1,2,4-trichlorobenzene in rats.

1,2,4-Trichlorobenzene (TCB) labeled with C-14 was given perorally to rats at a dosage of 50 mg/kg for excretion and distribution studies. About 66% and 17% of the oral dose was excreted in the urine and feces, respectively, within 7 days. Trapped radioactivity in the expired air amounted to 2.1% of the dose, but production of labeled carbon dioxide was negligible. Tissue residues were evenly distributed throughout the organs and tissues examined, except for the adipose tissue which consistently had a little higher concentration. The urinary, fecal and expiratory metabolites were identified. Free 2,4,5- and 2,3,5-trichlorophenol (TCP) and their conjugates were mainly detected in the urine. 5- or 6-Sulfhydryl, methylthio, methylsulfoxide and methylsulfone derivatives of TCB were also detected as minor metabolites. Dichlorobenzenes and unchanged TCB were confirmed in the expired air. Reductive dechlroination seems to be catalysed by intestinal microflora enzymes.

Characterization of a xenobiotic thiol methyltransferase and its role in detoxication in Tetrahymena thermophila

The protozoan Tetrahymena thermophila produces pentachlorobenzenethiol as an intermediate during the metabolism of the fungicide pentachloronitrobenzene. A thiol methyltransferase which catalyzes the S-adenosylmethionine-dependent methylation of pentachlorobenzenethiol has been detected in extracts from this organism. The enzyme was localized in the cytoplasm, and has been purified 130-fold. It has a molecular weight of 41,000 and a pH optimum of 7.5. A number of foreign thiols, but not the cellular thiols, glutathione or cysteine, were substrates for the enzyme. Phenols and anilines were not substrates. With pentachlorobenzenethiol as the methyl acceptor the apparent K m was 27 μ M, and the K m for S-adenosylmethionine was 110 μ M. To determine if the enzyme could play a role in the detoxication of reactive thiols, toxicity tests were carried out with a variety of aromatic thiols and their corresponding methylthio derivatives. In addition, toxicity tests on some corresponding phenols and anilines were carried out. In general, in long-term tests the aromatic thiols were more toxic than the methylthio derivatives, and intermediate in toxicity between phenols and anilines. In short-term tests the toxicity of aromatic thiols was enhanced by pretreatment with dithiothreitol suggesting that the thiol/disulfide status is an important factor in thiol toxicity. Exposure of T. thermophila to sublethal levels of pentachlorobenzenethiol resulted in an adapted population of cells with increased levels of thiol methyltransferase, and decreased sensitivity to aromatic thiols.

METHOXY AND METHYLTHIO DERIVATIVES OF TETRAKIS(TRIFLUOROMETHYL)-SPIRO [1,3,2λ5-DIOXAPHOSPHOLANE-2,2′[1,3,2λ5] DIOXAPHOSPHOLANE

Abstract 2-Chloro-1,3,2-dioxaphospholane 1 reacted with ammonium perfluoropinacolate 2 to give the stable tetraoxa(hydro)spirophosphorane 3, which upon u.v. irradiation in the presence of dimethyldisulfide yielded the methylthio derivative 8. Compound 8 was available also from 2-methylthio-1,3,2-dioxaphospholane 7 and hexafluoroacetone whereas 2-methoxy-1,3,2-dioxaphospholane 4 furnished a 1 : 1 mixture of the 1,3,2λ5 and 1,3,4λ5-dioxaphospholane, 5 and 6. Bis(trimethylsilyl)ethyleneglycolether 11 and 2,2-difluor-2-methylthio-4,4,5,5-tetrakis(trifluoromethyl)-1,3,2λ5-dioxaphospholane 9 did not form 8. The 1H NMR spectrum of 3 was analyzed as an AA'BB'X spin system. A 19F-19 F homocorrelated 2 D spectrum indicated a 2-CF3 … 5-F3C coupling interaction, probably via a non-bond mechanism.