- Reagent-installed capsule network: Selective thiocarbamoylation of aromatic amines in crystals with preinstalled CH3NCS
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Crystalline reagent capsules were prepared by installing CH3NCS into networked molecular capsules. While the tight encapsulation completely prevented leaching of reagent molecules into the supernatant, introduction of amines into the interstitial pores triggered reagent delivery. As a result, enhanced substrate selectivity was observed in crystalline-state thiocarbamoylation (see picture; 86:14 in favor of 2- vs. 1-naphthylamine). Copyright
- Inokuma, Yasuhide,Ning, Guo-Hong,Fujita, Makoto
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Read Online
- Conformation of some N,N'-arylalkyl thioureas by 1H-NMR and infrared spectral analysis
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Several N,N'-arylalkyl thioureas were examined with 1H-NMR and i.r. spectra in order to study the conformation of the -NHCSNH- group.The influence of temperature and substituents on the chemical shift of the N-H protons has been investigated.Formation of a strong intramolecular hydrogen bond stabilizes the trans-cis conformation for most systems, while for the others the prevalence of different rotational isomers can be postulated.The influence of the steric effect on hydrogen bonding and molecular conformation is discussed.
- Sudha, L. V.,Sathyanarayana, D. N.
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Read Online
- Development of phenylthiourea derivatives as allosteric inhibitors of pyoverdine maturation enzyme PvdP tyrosinase
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Infections caused by Pseudomonas aeruginosa become increasingly difficult to treat because these bacteria have acquired various mechanisms for antibiotic resistance, which creates the need for mechanistically novel antibiotics. Such antibiotics might be developed by targeting enzymes involved in the iron uptake mechanism because iron is essential for bacterial survival. For P. aeruginosa, pyoverdine has been described as an important virulence factor that plays a key role in iron uptake. Therefore, inhibition of enzymes involved in the pyoverdine synthesis, such as PvdP tyrosinase, can open a new window for the treatment of P. aeruginosa infections. Previously, we reported phenylthiourea as the first allosteric inhibitor of PvdP tyrosinase with high micromolar potency. In this report, we explored structure-activity relationships (SAR) for PvdP tyrosinase inhibition by phenylthiourea derivatives. This enables identification of a phenylthiourea derivative (3c) with a potency in the submicromolar range (IC50 = 0.57 + 0.05 μM). Binding could be rationalized by molecular docking simulation and 3c was proved to inhibit the bacterial pyoverdine production and bacterial growth in P. aeruginosa PA01 cultures.
- Dekker, Frank J.,Quax, Wim J.,Voet, Julian M.,Wibowo, Joko P.,Xiao, Zhangping
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supporting information
(2020/07/21)
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- CHEMICAL MODULATORS OF STORE-OPERATED CALCIUM CHANNELS AND THEIR THERAPEUTIC APPLICATIONS
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Methods of identification of inhibitors of calcium release-activated calcium (CRAC) channel and small molecule inhibitors of CRAC channel, including methods of their synthesis and pharmaceutical use, are disclosed.
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Paragraph 0130
(2019/04/14)
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- Nickle Catalysis Enables Access to Thiazolidines from Thioureas via Oxidative Double Isocyanide Insertion Reactions
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An efficient synthesis of thiazolidine-2,4,5-triimine derivatives was developed via Ni-catalyzed oxidative double isocyanide insertion to thioureas under air conditions, in which thioureas play three roles as a substrate, a ligand, and overcoming isocyanide polymerization. The reaction is featured by employing a low-cost and low loading Ni(acac)2 catalyst, without any additives, and high atom economy. This is the first example to directly apply a Ni(II) catalyst in oxidative double isocyanide insertion reactions.
- Yuan, Wen-Kui,Liu, Yan Fang,Lan, Zhenggang,Wen, Li-Rong,Li, Ming
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supporting information
p. 7158 - 7162
(2018/11/25)
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- Antileishmanial thioureas: Synthesis, biological activity and in Silico evaluations of new promising derivatives
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Leishmaniasis is a neglected tropical disease caused by protozoan parasites belonging to the genus Leishmania. Currently, the drugs available for treatment of this disease present high toxicity, along with development of parasite resistance. In order to overcome these problems, efforts have been made to search for new and more effective leishmanicidal drugs. The aim of this study was to synthesize and investigate the leishmanicidal effect of N,N′-disubstituted thioureas against Leishmania amazonensis, with evaluation of their in silico pharmacokinetics and toxicity profiles. Our results showed that different thioureas could be obtained in high to moderate yields using simple reaction conditions. Nine thiourea derivatives (3e, 3i, 3k, 3l, 3p, 3q, 3v, 3x and 3z) were active against parasite promastigotes (IC50 21.48–189.10μM), with low cytotoxicity on mice peritoneal macrophages (CC50>200μM), except for thiourea 3e (CC50=49.22μM). After that, the most promising thioureas (3k, 3l, 3p, 3q and 3v) showed IC50 ranging from 70 to 150μM against L. amazonensis amastigotes in infected macrophages. Except for thiourea 3p, the leishmanicidal activity of the derivatives were independent of nitric oxide (NO) production. Thioureas 3q and 3v affected promastigotes cell cycle without disturbing the mitochondrial membrane potential. Furthermore, our derivatives showed satisfactory theoretical absorption, distribution, metabolism, excretion, toxicity (ADMET) properties. These data indicate that thiourea derivatives are good candidates as leading compounds for the development of new leishmanicidal drugs.
- Viana, Gil Mendes,Do Amaral, Lilian Henriques,Meireles, Paloma Wetler,Nunes, Raquel Pinto,Da Silva, Luiz Cláudio Rodrigues Pereira,De Sousa, Valeria Pereira,Sathler, Plínio Cunha,Cabral, Lucio Mendes,Soares, Deivid Costa,Saraiva, Elvira Maria,Santana, Marcos Vinicius,Castro, Helena Carla,De Sequeira Aguiar, Lúcia Cruz,Rodrigues, Carlos Rangel,Abreu, Paula Alvarez
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p. 911 - 919
(2018/10/31)
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- Synthesis and antiplatelet activity of antithrombotic thiourea compounds: Biological and structure-activity relationship studies
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The incidence of hematological disorders has increased steadily in Western countries despite the advances in drug development. The high expression of the multi-resistance protein 4 in patients with transitory aspirin resistance, points to the importance of finding new molecules, including those that are not affected by these proteins. In this work, we describe the synthesis and biological evaluation of a series of N,N′-disubstituted thioureas derivatives using in vitro and in silico approaches. New designed compounds inhibit the arachidonic acid pathway in human platelets. The most active thioureas (compounds 3d, 3i, 3m and 3p) displayed IC50 values ranging from 29 to 84 μM with direct influence over in vitro PGE2 and TXA2 formation. In silico evaluation of these compounds suggests that direct blockage of the tyrosyl-radical at the COX-1 active site is achieved by strong hydrophobic contacts as well as electrostatic interactions. A low toxicity profile of this series was observed through hemolytic, genotoxic and mutagenic assays. The most active thioureas were able to reduce both PGE2 and TXB2 production in human platelets, suggesting a direct inhibition of COX-1. These results reinforce their promising profile as lead antiplatelet agents for further in vivo experimental investigations.
- Louren?o, André Luiz,Saito, Max Seidy,Dorneles, Luís Eduardo Gomes,Viana, Gil Mendes,Sathler, Plínio Cunha,De Aguiar, Lúcia Cruz Sequeira,De Pádula, Marcelo,Domingos, Thaisa Francielle Souza,Fraga, Aline Guerra Manssour,Rodrigues, Carlos Rangel,DeSousa, Valeria Pereira,Castro, Helena Carla,Cabral, Lucio Mendes
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p. 7174 - 7200
(2015/05/06)
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- Synthesis and characterisation of [(en)2Co]3+ complexes coordinated by substituted thiourea ligands
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Substituted thiourea ligands bind in a bidentate manner forming a four-membered ring through the sulfur atom and a deprotonated thiourea nitrogen atom when reacted with [(en)2Co(OSO2CF3)2]+ in tetramethylene sulfone. Reaction of unsymmetrical ligands results in the formation of coordination isomers, some of which can be separated by column chromatography using Sephadex SPC-25. Coordination isomers are easily distinguishable based on visible and 1H NMR spectroscopy . Twelve para-substituted and one meta-substituted ligands were studied: N,N′-dibenzylthiourea (1a); N-(R)phenyl-N′-benzylthiourea R≤H (2a), NO2 (2b), CH3 (2c); N-(R)phenyl-N′-(R′)phenylthiourea R, R′: H, H (3a), H, CH3 (3b), OCH3, NO2 (3c), CH3, NO2 (3d); N-methyl-N′-(R)phenylthiourea R≤H (4a), CH3 (4b), OCH3 (4c), NO2 (4d), 3-CH3 (4e). The solid state structure (X-ray) of one isomer of Co-4a as its perchlorate salt confirms the coordination mode suggested by 1H NMR spectroscopy and shows that the Co-N bond trans to the coordinated thiourea sulfur induces a structural trans effect of 0.019A.
- Roecker, Lee,Aiyegbo, Mohammed,Al-Haddad, Aladdin,Fletcher, Emily,Kc, Ravi,Hurst, Jason,Lane, Timothy,Larsen, Ryan,Noinaj, Nicholas,Teh, Say Lee,Wade, Samuel K.,Parkin, Sean
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p. 944 - 951
(2013/09/12)
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- A versatile thiouronium-based solid-phase synthesis of 1,3,5-triazines
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A thiouronium-based solidphase synthesis of a 1,3,5-triazine scaffold has been developed. The key feature of the synthesis is the use of a readily accessible solid-supported thiouronium salt as a primary precursor for the stepwise assembly of the 1,3,5-tri-azine substrate. The sulfur linker employed in the synthesis is stable under both acidic and basic conditions and is versatile enough to provide access to monocyclic, bicyclic, and spirocyclic compounds with the 1,3,5-triazine scaffold. By using this synthetic strategy, a representative set of 79 compounds containing the 1,3,5-triazine scaffold were prepared.
- Kong, Kah Hoe,Tan, Chong Kiat,Lin, Xijie,Lam, Yulin
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experimental part
p. 1476 - 1486
(2012/03/26)
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- Microwave-assisted synthesis of symmetrical and unsymmetrical N,N 0-disubstituted thioureas and ureas over MgO in dry media
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Under mild microwave irradiation conditions a variety of symmetrical and unsymmetrical A,N′-disubsti-tuted thioureas and ureas were prepared via the reaction of Af-monosubstituted hydroxylamines with isocyanate and isothiocyanate derivatives over MgO under solvent-free conditions. This new method afforded satisfactory results with good yields, short reaction time, and simplicity in the experimental procedure.
- Valizadeh, Hassan,Dinparast, Leila
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experimental part
p. 251 - 254
(2012/07/01)
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- Structural requirement of phenylthiourea analogs for their inhibitory activity of melanogenesis and tyrosinase
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Effect of a series of 1-phenylthioureas 1a-k and 1,3-disubstituted thioureas 2a-k were evaluated against melanin formation in melanoma B16 cell line and mushroom tyrosinase. Inhibitory activity of tyrosinase of 1-phenylthioureas 1a-k is parallel to their melanogenic inhibition. Thus, the melanogenic inhibition in melanoma B16 cells of 1-phenylthioureas could be the result of inhibition of tyrosinase. However, 1,3-diaryl or 1-phenyl-3- alkylthioureas, 2a-k, appears as melanogenic inhibitor without inhibition of tyrosinase. The molecular docking study of 1e and 2b to binding pocket of tyrosinase provided convincing explanation regarding the necessity of direct connection of planar phenyl to thiourea unit without N′-substitution of phenylthioureas 1 as tyrosinase inhibitor and 2 as non-tyrosinase inhibitor.
- Thanigaimalai, Pillaiyar,Lee, Ki-Cheul,Sharma, Vinay K.,Joo, Cheonik,Cho, Won-Jea,Roh, Eunmiri,Kim, Youngsoo,Jung, Sang-Hun
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experimental part
p. 6824 - 6828
(2011/12/22)
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- Clean photodecomposition of 1-methyl-4-phenyl-1 H-tetrazole-5(4 H)-thiones to carbodiimides proceeds via a biradical
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The photochemistry of 1-methyl-4-phenyl-1H-tetrazole-5(4H)-thione (1a) and 1-(3-methoxyphenyl)-4-methyl-1H-tetrazole-5(4H)-thione (1b) was studied in acetonitrile at 254 and 300 nm, which involves expulsion of dinitrogen and sulfur to form the respective carbodiimides 5a,b as sole photoproducts. Photolysis of the title compounds in the presence of 1,4-cyclohexadiene trap led to the formation of respective thioureas, providing strong evidence for the intermediacy of a 1,3-biradical formed by the loss of dinitrogen. In contrast, a trapping experiment with cyclohexene provided no evidence to support an alternative pathway of photodecomposition involving initial desulfurization followed by loss of dinitrogen via the intermediacy of a carbene. Triplet sensitization and triplet quenching studies argue against the involvement of a triplet excited state. While the quantum yields for the formation of the carbodiimides 5a,b were modest and showed little change on going from a C 6H5 (1a) to mOMeC6H4 (1b) substituent on the tetrazolethione ring, the highly clean photodecomposition of these compounds to a photostable end product makes them promising lead structures for industrial, agricultural, and medicinal applications.
- Alawode, Olajide E.,Robinson, Colette,Rayat, Sundeep
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experimental part
p. 216 - 222
(2011/03/18)
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- Synthesis and anticonvulsant activity of new N-1′,N-3′-disubstituted-2′H,3H,5′H-spiro-(2-benzofuran-1,4′-imidazolidine)-2′,3,5′-triones
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Thirteen new N-1′,N-3′-disubstituted-2′H,3H,5′H-spiro-(2-benzofuran-1,4′-imidazolidine)-2′,3,5′-triones were synthesized and their pharmacological activity determined with the objective to better understand their SAR for anticonvulsant activity. The anticonvulsant effects of these compounds were evaluated by standard pentylenetetrazol (scPTZ test) and maximum electroshock seizure (MES test) models in mice. Most of the compounds showed ability to protect against the pentylenetetrazol-induced convulsions. Compound 3o (the N-1′-p-nitrophenyl, N-3′-ethyl derivative) in the N-1′-aryl, N-3′-alkyl disubstituted series exhibited maximum activity with ED50 of 41.8 mg/kg in scPTZ convulsion model.
- Patel, Hardik J.,Sarra, Joe,Caruso, Francesco,Rossi, Miriam,Doshi, Utkarsh,Stephani, Ralph A.
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p. 4644 - 4647
(2007/10/03)
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- Synthesis and biological evaluation of 3-benzyl-1-methyl- and 1-methyl-3-phenyl-isothioureas as potential inhibitors of iNOS
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Novel benzyl- and phenyl-isothioureidic derivatives have been synthesised and evaluated as inhibitors of nitric oxide synthesis, induced in lipopolysaccharide (LPS)-activated J774.A1 macrophage cell line. The most potent iNOS inhibitor resulting was 1-methyl-3-phenyl-S-methyl isothiourea 5l.
- Paesano, Nicola,Marzocco, Stefania,Vicidomini, Caterina,Saturnino, Carmela,Autore, Giuseppina,De Martino, Giovanni,Sbardella, Gianluca
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p. 539 - 543
(2007/10/03)
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- Applicability of a modified Edman procedure for measurement of protein adducts: Mechanisms of formation and degradation of phenylthiohydantoins
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Adducts to N-terminal valine residues in hemoglobin (Hb) are used for monitoring in vivo doses of electrophiles and are quantitated by means of a modified Edman procedure, the "N-alkyl Edman procedure". In the reaction with pentafluorophenyl isothiocyanate, N-alkylated valines cyclize and detach from the protein as pentafluorophenylthiohydantoins (PFPTHs) much more efficiently than do unsubstituted N-terminal valine residues. The mechanisms of this reaction, and of possible degradation reactions, have been studied with model compounds using phenyl- and pentafluorophenyl isothiocyanate. The rapid cyclization to N-alkylvaline-PTHs occurs as a consequence of the influence of substituents on ring formation. This facilitated cyclization favors a direct attack by the thiocarbamoyl nitrogen atom on valine-C-1, and is also observed to occur slowly at unsubstituted N-terminal valines. Such cyclization is favored in protic solvents. Under alkaline conditions and in the presence of air, hydrolytic and oxidative processes give rise to degradation products. The PTH derivatives of N-alkylvaline are less apt to undergo such reactions than are the corresponding derivatives of unsubstituted valine. We conclude that the presence of an N-substituent exerts a greater influence on the cyclization process than the structure of the amino acid or of the Edman reagent. For adducts of different structures, the method has broad applicability, for which the limits, however, are not yet explored. The knowledge from the studies is valid not only for the N-alkyl Edman procedure, but also, to some extent, for the classical Edman degradation reaction. The oxidative side reaction gave rise to the invention of a novel synthesis route for insertion of nucleophiles at carbon-5 in thiohydantoins. The present investigation provides a basis for the N-alkyl Edman procedure, facilitating new toxicological applications.
- Rydberg, Per,Luening, Bjoern,Wachtmeister, Carl Axel,Eriksson, Lars,Toernqvist, Margareta
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p. 570 - 581
(2007/10/03)
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- 1-(Methyldithiocarbonyl)imidazole: A useful thiocarbonyl transfer reagent for synthesis of substituted thioureas
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1-(Methyldithiocarbonyl)imidazole 1 and its N-methyl quaternary salt 2 have been shown to be efficient methyldithiocarbonyl and thiocarbonyl transfer reagents for the synthesis of dithiocarbamates, symmetrical and unsymmetrical mono-, di- and tri-substituted thioureas in high yields under mild and simple non-hazardous reaction conditions. (C) 2000 Elsevier Science Ltd.
- Mohanta, Pramod K.,Dhar, Sanchita,Samal,Ila,Junjappa
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p. 629 - 637
(2007/10/03)
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- A convenient route to cyanoguanidines
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A facile and versatile method for the preparation of cyanoguanidines 7 from amines 3 and isothiocyanates 4 via a methylation, cyanamide-treatment sequence is described.
- Novak, Lajos,Hanania, Michel,Kovacs, Peter,Kovacs, Csilla Erika,Kolonits, Pal,Szantay, Csaba
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p. 1757 - 1766
(2007/10/03)
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- Substituted N-phenylisothioureas: Potent inhibitors of human nitric oxide synthase with neuronal isoform selectivity
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S-Ethyl N-phenylisothiourea (4) has been found to be a potent inhibitor of both the human constitutive and inducible isoforms of nitric oxide synthase. A series of substituted N-phenylisothiourea analogues was synthesized to investigate the structure-activity relationship of this class of inhibitor. Each analogue was evaluated for human isoform selectivity. One analogue, S-ethyl N-[4-(trifluoromethyl)phenyl]isothiourea (39), exhibited 115-fold and 29-fold selectivity for the neuronal isoform versus the inducible and endothelial derived constitutive isoforms, respectively. Studies have shown the substituted N-phenylisothiourea 39 binds competitively with L,-arginine.
- Shearer, Barry G.,Lee, Shuliang,Oplinger, Jeffrey A.,Frick, Lloyd W.,Garvey, Edward P.,Furfine, Eric S.
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p. 1901 - 1905
(2007/10/03)
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- A facile synthesis of 2-N(methyl amino) benzothiazoles
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Reaction of aromatic primary amines with methylisothiocyanate (MITC) yielded N-methyl-N1-(benzelene-1-yl)thioureas which underwent oxidative cyclization in the presence of bromine in acetic acid, at room temperature, affording the title compounds.
- Ambati, Narahari Babu,Anand,Hanumanthu
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p. 1487 - 1493
(2007/10/03)
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- Structure and hydrogen bonding of solid N1-alkyl-N2-arylthioureas. 13C CP/MAS, IR and semi-empirical AM1 studies
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Seven crystalline N1-alkyl-N2-arylthioureas were studied by 13C CP/MAS NMR and by IR spectroscopy. The double set of signals in 13C CP/MAS spectra indicates that molecules of N1-ethyl-N2-(3-methylphenyl)thiourea and N1-ethyl-N2-(4-methylphenyl)thiourea are crystallographically non-equivalent. N1-Propene-N1-phenylthiourea forms cyclic dimers with two N2-H...S hydrogen bonds, as confirmed recently by x-ray diffraction. The broad vNH maxima at 3175-3295 cm-1 in the IR spectra indicate that in other thioureas both N1-H and N2-H protons are involved in hydrogen bonding and that the non-bonded N1-H proton in cyclic dimers of N1-propenethioureas is probably an exception. Semi-empirical AM1 calculations showed that the N2-H proton is more positively charged than the N1-H proton and therefore should be preferentially involved in N2-H...S hydrogen bonds.
- Wawer, Iwona,Koleva, Vera
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p. 207 - 212
(2007/10/03)
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- A facile conversion of symmetrical to unsymmetrical thioureas
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A convenient route for quantitative conversion of symmetrical thioureas into unsymmetrical thioureas is described. The method circumvents the use of toxic isothiocyanates and a case study is reported using 1,3-diphenylthiourea.
- Ramadas,Srinivasan,Janarthanan
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p. 6447 - 6450
(2007/10/02)
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- Estimation of Charge Transfer Parameters of Complexes of Substituted Thioureas with Iodine
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A biquadratic equation in the variable b/a has been derived from Mulliken's theory of charge transfer(CT) complexes.The equation gives b/a values close to those obtained from the dipole moments of CT complexes.The solution of the equation makes use of the values of the frequency (νCT) of the CT band, the enthalpy (ΔH) of formation, obtained spectrophotometrically, for the complexes and assumed values for the overlap integral (S01).The energies of the no-bond and dative states, the resonance energies in the ground and excited states, the degree of CT in the ground state, the donor-acceptor distances in a series of complexes of thioureas with iodine and dipole moments of some of these complexes have been calculated from the values of a, b, a*, b*, S01, hνCT and ΔH with the help of the equations derived from Mulliken's theory by applying variational principle.The calculated values of the energy parameters correlate well with the strength of the complex as measured by the values of their equilibrium constants.The ionization potentials of the thioureas have also been determined.
- Seal, B. K.,Banerjee, B.,Mukherjee, D. C.
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p. 799 - 802
(2007/10/02)
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- KINETICS AND MECHANISM OF REARRANGEMENT AND METHANOLYSIS OF ACYLPHENYLTHIOUREAS
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S-Acyl-1-phenylthioureas and their 3-methyl derivatives are rearranged to 1-acyl derivatives of thiourea in methanolic solution.The rearrangement of the 1-acyl-1-phenyl derivative to the thermodynamically more stable 3-acyl derivative is subject to specific base catalysis.The rearrangement of acetyl group is about 2 orders of magnitude slower than that of benzoyl group. 1-Acetyl-1-phenylthiourea undergoes base-catalyzed methanolysis (giving phenylthiourea and methyl acetate) instead of the rearrangement.The methanolysis rates of 1-acyl-3-phenylthioureas and their N-methyl derivatives have been measured.The acetylthioureas react at most 3 x faster than the benzoyl derivatives.The methyl group at the nitrogen adjacent to acyl group accelerates the solvolysis by almost 2 orders of magnitude; the methyl group at the other nitrogen atom retards the solvolysis by almost 1 order of magnitude.Replacement of hydrogen atom by methyl group at the phenyl-substituted nitrogen increases acidity of the phenylacetylthiourea by 2 orders of magnitude.The same replacement at the benzoyl-substituted nitrogen increases the acidity by 3 orders of magnitude, the increase in the case of the acetyl derivative being as large as 4 orders of magnitude.
- Kavalek, Jaromir,Jirman, Josef,Sterba, Vojeslav
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p. 766 - 778
(2007/10/02)
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- Derivatives of Imidazolidines from Oxalic Amidines
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Tetraarylsubstituted oxalic amidines 1 react with acyl chlorides, phosgene, thiophosgene, chlorocarbonylsulfenylchloride, isocyaniddichlorides, and N-aroyl-1-chlorothio-formimidoylchlorides 7 to give the corresponding 5-membered heterocycles 3,4,5 and 8.Isocyanates 9 and isothiocyanates 10 react with oxalic amidines to yield imidazolidines 11, 12 and ureas 13, 14.Hydrolysis of 3-5, 8, 11, 12 leads to the corresponding oxo compounds 15, 16.
- Beckert, R.,Mayer, R.
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p. 227 - 236
(2007/10/02)
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