Monosubstituted Thioureas Research Articles

Synthesis and structure–activity relationship studies of mono- and bis-thiourea derivatives featuring halogenated azo dyes with antimicrobial properties

A series of mono-substituted thiourea (2a–i) and bis-substituted thiourea-azo (3a–f) derived from paracetamol derivatives were prepared from isothiocyanates with one and two equivalents of halogenated azo dyes, respectively. The incorporation of azo-derived paracetamol via thiourea moiety in 2a–i depicted excellent microbial activity on Staphylococcus aureus, and 2-(((3-((2-bromophenyl)diazenyl)-4-hydroxyphenyl)carbamothioyl)carbamoyl)phenyl acetate, 2a showed equivalent inhibition properties to the standard ampicillin (10 mm). The structure–activity relationship studies of 2a were supported via molecular docking interaction against S. aureus tyrosyl-tRNA synthetase protein which displayed a free energy interaction of −7.7 kcal/mol compared to aspirin (−6.4 kcal/mol).

Revealing the Interplay Between Covalent and Non-Covalent Interactions Driving the Adsorption of Monosubstituted Thiourea Derivatives on the Au(111) Surface

This work reports a detailed study of the adsorption of thiourea and seven monosubstituted thiourea derivatives on the Au(111) surface based on self-consistent periodic density functional theory (D...

N-monoarylacetothioureas as potent urease inhibitors: synthesis, SAR, and biological evaluation

A urease inhibitor with good in vivo profile is considered as an alternative agent for treating infections caused by urease-producing bacteria such as Helicobacter pylori. Here, we report a series of N-monosubstituted thioureas, which act as effective urease inhibitors with very low cytotoxicity. One compound (b19) was evaluated in detail and shows promising features for further development as an agent to treat H. pylori caused diseases. Excellent values for the inhibition of b19 against both extracted urease and urease in intact cell were observed, which shows IC50 values of 0.16 ± 0.05 and 3.86 ± 0.10 µM, being 170- and 44-fold more potent than the clinically used drug AHA, respectively. Docking simulations suggested that the monosubstituted thiourea moiety penetrates urea binding site. In addition, b19 is a rapid and reversible urease inhibitor, and displays nM affinity to urease with very slow dissociation (k off=1.60 × 10−3 s−1) from the catalytic domain.

Green synthesis and structural characterization of novel N1-substituted 3,4-dihydropyrimidin-2(1H)-ones

Abstract Novel N1-substituted 3,4-dihydropyrimidin-2(1H)-one derivatives were synthesized through Biginelli condensation of aromatic aldehydes, β-ketoesters, and monosubstituted (thio)ureas in the presence of copper methanesulfonate at 90°C under solvent-free conditions. The screening of the catalysts showed the copper methanesulfonate was the best. Its catalytic activity remained after three times of use. The products were characterized by IR, 1H NMR, 13C NMR, elemental analysis, and X-ray single crystal diffraction technique. A reasonable reaction mechanism was proposed.

Thiazol-4-one derivatives from the reaction of monosubstituted thioureas with maleimides: structures and factors determining the selectivity and tautomeric equilibrium in solution.

2-(Alkyl(aryl)amino)thiazol-4(5H)-ones can regioselectively be prepared from monoalkyl(aryl)thioureas and maleimides. In solution, the former heterocycles exist in a tautomeric equilibrium with 2-(alkyl(aryl)imino)thiazolidin-4-ones and the substituent on the exocyclic nitrogen atom governs the ratio of these tautomers. Isomers with the alkyl group in the endocyclic position can be obtained from N-methyl(ethyl)thioureas. 2D NMR spectroscopy and DFT calculations rationalize experimental results.

ChemInform Abstract: Synthesis of Monosubstituted Thioureas by Vapour Digestion and Mechanochemical Amination of Thiocarbamoyl Benzotriazoles.

AbstractHighly deactivated anilines, such as 4‐nitro and 4‐cyano are not applicable as substrates.

Synthesis of monosubstituted thioureas by vapour digestion and mechanochemical amination of thiocarbamoyl benzotriazoles

N-monosubstituted thioureas have been rapidly accessed from thiocarbamoyl benzotriazoles by ammonia vapour digestion and solvent-free mechanochemical milling in near-quantitative yields.

Hepatitis C virus serine protease: synthesis of radioactive and stable isotope‐labeled potent inhibitors

Drug candidates labeled with radioactive and stable isotopes are required for absorption, distribution, metabolism, and excretion (ADME) studies, pharmacokinetics, autoradiography, bioanalytical, and other research activities. The findings from these studies are crucial in the development of a drug candidate and its approval for human use. Herein, we report the synthesis of potent and selective hepatitis C virus serine protease inhibitors related to BILN 2061 and BI 201335 labeled with radioactive and stable isotopes. Synthetic efforts were focused on the common substituted thiazole moiety, which is easily accessible via a Hantzsch's reaction of α-bromoketones and mono-substituted thioureas. In the radioactive synthesis, commercially available carbon-14 thiourea was utilized to prepare mono-substituted thioureas, which upon condensation with α-bromoketones in isopropanol followed by ester hydrolysis gave the desired carbon-14-labeled protease inhibitors. The same strategy was used to prepare these inhibitors labeled with stable isotopes. Mono-substituted thioureas were obtained from commercially available deuterium-labeled intermediates and then condensed with α-bromoketones followed by ester hydrolysis to give the deuterium-labeled inhibitors.

C-S Bond-Forming Reactions of Barbiturylbromide with Isothiocarbamides in Aqueous Media

The C-S cross coupling of pharmaceutically active barbituric acid derivatives has been achieved by the interaction of selective monobromobarbituric acid with thioureas in an aqueous medium. This method is applicable for simple thiourea as well as monosubstituted thioureas, and corresponding products are obtained in good yield. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]

It is ‘thiazolidine-2,4-dione’ and not thiohydantoins as the reaction product of monosubstituted thioureas and chloroacetylchloride

The mechanism of thiazole-2-imine formation has not been well understood leading to the proposal of incorrect structures for the products obtained by the reaction of thiourea analogs with α -haloke...

Reaction of 3-aminoquinoline-2,4-diones with isothiocyanic acid—an easy pathway to thioxo derivatives of imidazo[1,5-c]quinazolin-5-ones and imidazo[4,5-c]quinolin-4-ones

Abstract 3-Amino-1 H ,3 H -quinoline-2,4-diones react with thiourea or potassium thiocyanate in boiling acetic acid to give novel 2,3-dihydro-3-thioxoimidazo[1,5- c ]quinazolin-5(6 H )-ones in high yields. However, if the starting compounds are substituted with a benzyl group at position 3, a C-debenzylation proceeds to give 2,3-dihydro-2-thioxo-1 H -imidazo[4,5- c ]quinolin-4(5 H )-ones. According to a proposed reaction mechanism, a molecular rearrangement of the primarily formed mono-substituted thiourea takes place. All compounds were characterized by 1 H, 13 C and 15 N NMR and IR spectroscopy as well as by mass spectrometry.

Synthesis of Furo[2,3‐d]pyrimidines Using Inorganic Solid Support.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of Alkyl- and Phenyl-2-thiouracils and 1,3-Thiazin-4-ones by Nucleophilic Substitution of Unsymmetrical Thioureas with 3-Chloropropenoates

Unsymmetrically substituted thioureas and ethyl (E)- and (Z)-3-aryl-3-chloro-2-cyano- propenoates (1a) and (1b) gave after nucleophilic vinylic substitution and cyclisation two isomers of 1,3-disubstituted 6-aryl-5-cyano-2-thiouracil derivatives, 3a-3i and 4a-4i. Substituted 1,3-thiazin-4-ones 5a-5d were formed in moderate to good yields when monosubstituted thioureas were allowed to react under similar conditions.

Cytotoxicity of a series of mono- and di-substituted thiourea in freshly isolated rat hepatocytes: a preliminary structure-toxicity relationship study

The cytotoxicity of a series of 12 mono- and 4 di-substituted thiourea containing compounds in freshly isolated rat hepatocytes was investigated. It was found that thiourea toxicity, as evidenced by an increase in LDH-leakage from the cells, was accompanied by a depletion of intracellular glutathione (GSH). No increase in lipid peroxidation was observed with any of the thiourea. Burimamide and thioperamide, thiourea-containing histamine receptor ligands, were also found to deplete intracellular GSH. A clear structure-toxicity relationship was uncovered among a homologous series of N-phenylalkylthiourea. N-benzylthiourea (BTU) and N-phenylethylthiourea (PETU) were found to be non-toxic at a concentration of 1 mM, while N-phenylpropylthiourea (PPTU) and N-phenylbutylthiourea (PBTU) were found to cause significant LDH-leakage from the cells, accompanied by a depletion of intracellular GSH. This structure-toxicity relationship was further investigated using hepatocytes of differentially induced rats, however, no significantly different results were obtained when using hepatocytes of rats induced with phenobarbital (PB) or β-naphthoflavone (BNF). Oxidation of the thiourea moiety is thought to be the first step in the bioactivation of thiourea containing compounds. The oxidation of thiocholine sulfenic acids, produced by FMO-mediated oxidation of the thiourea moiety, was used to determine whether the compounds examined are substrates for the FMO enzymes in rat liver. No clear relationship was found between cytotoxicity of the mono-substituted thiourea and lipophilicity of the N-substituent, nor with the FMO-mediated oxidation of the thionosulfur atom of the mono-substituted thiourea. It is concluded from this study, that thiourea toxicity in rat hepatocytes is structure-dependent and manifests itself as LDH-leakage and as a depletion of intracellular non-protein sulfhydryls, notably GSH, most likely followed by alkylation of vital macromolecular structures.

Synthesis and Characterization of Rhenium(V) Oxo Complexes with a New Thiol-Amide-Thiourea Ligand System. X-ray Crystal Structure of [1-Phenyl-3-[2-((2-thioacetyl)amino)ethyl]thioureato]oxorhenium(V).

General methods for preparing Re(V)O complexes with a novel series of thiol-amide-thiourea (TATU) ligands, a new class of N(2)S(2) chelates, were developed. The TATU ligands, the first multidentate systems designed with a bidentate thiourea moiety, have been used to prepare the first high-valent transition metal complexes with bidentate thiourea coordination. Direct reaction of N-(2-aminoethyl)-2-((triphenylmethyl)thio)acetamide (1) with phenyl, 4-methoxyphenyl, 4-chlorophenyl, and methyl isothiocyanate afforded ready access to the corresponding S-protected TATU ligands in one step. A two-step preparation of the N,N-dimethylthiourea TATU ligand derived from 1 was also developed. Deprotection of thiols in trifluoroacetic acid with triethylsilane followed by a ligand exchange reaction with Re(V)O precursors yielded neutral ReO(TATU) complexes. The structure of [1-phenyl-3-[2-((2-thioacetyl)amino)ethyl]thioureato]oxorhenium(V) (6a) was determined by X-ray diffraction methods. Crystal data for 6a: C(11)H(12)N(3)O(2)ReS(2), fw 468.6, orthorhombic, Pca2(1); a = 22.605(5) Å, b = 13.029(3) Å, c= 9.698(2) Å; V = 2856.3(11) Å(3); Z = 8. The coordination environment of 6a was pseudo-square-pyramidal with a deprotonated thiol S, deprotonated amide N, deprotonated thiourea N, and thiocarbonyl S coordinated in the basal plane and the oxo ligand in the apical position. The thiourea function forms a four-membered chelate ring in the multidentate TATU ligands. The two N-C and the S-C bond distances within the monodeprotonated thiourea moiety were typical of bonds with multiple-bond character. Solution (1)H NMR data for all five complexes were consistent with the solid-state structure of 6a. A broad singlet attributable to the uncoordinated NH group of thiourea was observed for the monosubstituted thiourea complexes but was not present for the N,N-dimethylthiourea derivative. Instead, two singlets of equal intensity were observed for the two methyl groups, indicating that there is restricted rotation around the C-N(CH(3))(2) bond and an extended pi system in the thiourea moiety. The four-membered ring might cause difficulty because the M-S distance would be relatively long in an undistorted ligand. This may be the reason such chelate ligands have not been previously investigated. However, the N-C-S angle narrows to approximately 105 degrees, permitting a Re-S bond with a typical bond length to be formed. We conclude that such a ring represents a versatile new building block to create multidentate ligands.

Hydrogen bonds in N-(3-chloro-2-benzo[b]thienocarbonyl)- and N-(2-benzo[b]thienocarbonyl)-N'-monosubstituted thioureas

N-(3-Chloro-2-benzo[b]thienocarbonyl)-N'-monosubstituted thiourea derivatives undergo photocyclizations with lower yields than those obtained from analogous N',N'-disubstituted derivatives. This decreased reactivity is caused by the existence of a six-membered cyclic form with the very strong hydrogen bond NH···O=C. The possibility of formation of various conformers has been found with N-(2-benzo[b]thienocarbonyl)-N'-monosubstituted thiourea derivatives as a consequence of the rotation around the C(2)-C(O) connecting line.

Synthesis and efficient isolation procedure for gamma-linked fluorescein methotrexate.

Fluorescein isothiocyanate was reacted in dimethyl sulfoxide with a ten-fold excess of diaminopentane, and the mono-substituted thiourea product was isolated by DEAE-cellulose chromatography, lyophilization and acid precipitation from aqueous base. The dried product was then condensed in dry dimethyl sulfoxide with Methotrexate (MTX) activated by prior incubation (30 min) with 1-ethyl-3-(3'-dimethylaminopropyl) carbodiimide hydrochloride, and the reaction products were purified by column chromatography on DEAE-cellulose. Exhaustive elution with 1 M ammonium bicarbonate removed several by-products then finally afforded the exclusively gamma-linked fluorescein--MTX derivative. After lyophilization and acid-base precipitation the compound was obtained in good yield (greater than 40%), was homogeneous by reverse-phase HPLC epsilon 493 (0.1 N NaOH) = 66,000 and was a comparable inhibitor to MTX for rat-liver dihydrofolate reductase.

Photocyclization of N-(3-chloro-2-benzo[b]thienocarbonyl)-N'-monosubstituted thioureas

N-(3-Chloro-2-benzo[b]thienocarbonyl)-N'-monosubstituted thioureas, when irradiated with a high-pressure mercury discharge lamp through a pyrex or quartz filter, give the corresponding benzothienothiazine derivatives in lower yields than the analogous N',N'-disubstituted thioureas. The reactivity lowering of the N'-monosubstituted thioureas is ascribed to the intramolecular hydrogen bond C=O...H-N due to which these compounds in their ground states exist in the six-membered cyclic conformation unfavourable for the cyclization. The photolysis of N'-phenylthiourea results - due to a stronger hydrogen bond - in splitting of the molecule to give 3-chlorobenzo[b]thiophene-2-carboxamide and phenyl isothiocyanate.

Chemistry of metabolites of thioureas.

Thiourea and some monosubstituted thioureas are toxic and tumorogenic while 1,3-diarylthioureas are not. There are strong indications that the biological activity of these compounds is due to oxidation at sulfur followed by reactions in which the sulfur moiety is separated from the rest of the molecule. That is, the metabolism of toxic thioureas, involves this loss of sulfur while nontoxic compounds are either excreted unchanged or undergo alternate metabolism.1–3 The oxidation at sulfur is probably catalyzed by FAD-containing monooxygenase (FADMO). Model studies show that this enzyme oxidizes thioureas to the S-monoxide and S,S-dioxide. The slower oxidation in solution to the corresponding trioxides does not appear to be catalyzed by FADMO. 4,5 KeywordsNone NonePotassium CarbonateSlow OxidationSulfur MoietyAlternative Metabolic PathwayThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

A new method for converting thiourea and monosubstituted thioureas into cyanamides: desulphurisation by superoxide ion

Superoxide ion, in aprotic media, converts thiourea and monosubstituted thioureas into cyanamides.