Thiourea Bridge Research Articles

Supramolecular Cu(ii) nanoparticles supported on a functionalized chitosan containing urea and thiourea bridges as a recoverable nanocatalyst for efficient synthesis of 1H-tetrazoles.

A cost-effective and convenient method for supporting of Cu(ii) nanoparticles on a modified chitosan backbone containing urea and thiourea bridges using thiosemicarbazide (TS), pyromellitic dianhydride (PMDA) and toluene-2,4-diisocyanate (TDI) linkers was designed. The prepared supramolecular (CS-TDI-PMDA-TS-Cu(ii)) nanocomposite was characterized by using Fourier-transform infrared (FT-IR) spectroscopy, field emission scanning electron microscopy (FESEM), thermogravimetry/differential thermogravimetry analysis (TGA/DTA), energy-dispersive X-ray spectroscopy (EDS), EDS elemental mapping and X-ray diffraction (XRD). The obtained supramolecular CS-TDI-PMDA-TS-Cu(ii) nanomaterial was demonstrated to act as a multifunctional nanocatalyst for promoting of multicomponent cascade Knoevenagel condensation/click 1,3-dipolar azide-nitrile cycloaddition reactions very efficiently between aromatic aldehydes, sodium azide and malononitrile under solvent-free conditions and affording the corresponding (E)-2-(1H-tetrazole-5-yl)-3-arylacrylenenitrile derivatives. Low catalyst loading, working under solvent-free conditions and short reaction time as well as easy preparation and recycling, and reuse of the catalyst for five consecutive cycles without considerable decrease in its catalytic efficiency make it a suitable candidate for the catalytic reactions promoted by Cu species.

Tetrahydroquinoline units in flexible heteroarotinoids (Flex-Hets) convey anti-cancer properties in A2780 ovarian cancer cells

SHetA2 (NSC 721689), our lead Flex-Het anti-cancer agent, consists of a thiochroman (Ring A) and a 4-nitrophenyl (Ring B) linked by a thiourea bridge. In this work, several series of new analogs having a tetrahydroquinoline (THQ, Ring A) unit connected by a urea or thiourea linker to a 4-substituted phenyl (Ring B) have been prepared and evaluated relative to SHetA2 in terms of binding affinity with mortalin and inhibition of A2780 ovarian cancer cells. Six of the derivatives equaled or exceeded the efficacy shown by SHetA2. Compounds 1a-d (series 1), lacking a methyl on the Ring A nitrogen and the gem-dimethyls on the adjacent carbon, showed only weak activity. Salt 2, the quaternized N,N-dimethyl iodide salt analog of 1a, also possessed very modest growth inhibition in the cell line studied. Series 3 compounds, which had a C3 ketone and an N-methyl replacing the sulfur in Ring A, were most successful. Compound 3a [Ring A = 1,2,2,4,4-pentamethyl-3-oxo-1,2,3,4-tetrahydroquinolin-6-yl; urea linker; Ring B = 4-nitrophenyl] had slightly lower potency (IC50 3.8 μM), but better efficacy (94.8%) than SHetA2 (IC50 3.17 μM, efficacy 84.3%). In addition, 3c and 3d [urea and thiourea linkers, respectively; Ring B = 4-(trifluoromethyl)phenyl] and 3e and 3f [urea and thiourea linkers, respectively; Ring B = 4-(trifluoromethoxy)phenyl] were also evaluated since these agents possessed electron-withdrawing groups with H-bonding capability. All displayed good activity. Compounds 3c and 3e showed improvement in both potency and efficacy compared to SHetA2. In general, when the linker group between Rings A and B was a urea, efficacy values slightly exceeded those with a thiourea linker in the carbonyl-containing THQ systems 3a-g. In contrast, when Ring A possessed the 1,2,2,4,4-pentamethyl-3-hydroxytetrahydroquinolin-6-yl unit (4a-f, series 4), very modest potency and efficacy was observed. Model compound 5, an exact N-methyl THQ analog of SHetA2, demonstrated less potency (IC50 4.5 μM), but improved efficacy (91.7%). Modeling studies were performed to rationalize the observed results.

Merging periodic mesoporous organosilica (PMO) with mesoporous aluminosilica (Al/Si-PMO): A catalyst for green oxidation

Mesoporous aluminosilica is a unique structure for catalysis due to Lewis acidity of aluminum. Here, we design a new catalyst by merging periodic mesoporous organosilica with aluminosilica into its structure instead of mere silica. The employed organosilica bridge in this synthesis is a thiourea based organosiloxane precursor which has a unique feature in supporting catalytically active cations. Therefore, we support Cu2+ ions through these thiourea bridges to generate a catalytically active species along with aluminosilica structure (Cu@Al/Si-PMO-TU). Combining alminosilica with Cu2+ ions led to a synergistic catalytic activity in the aqueous oxidation of dibenzothiophene. Furthermore, the addition of Al3+ as a precursor during the synthesis of PMO causes an enhancement in the mesoporosity and surface area and led to the formation of mesoporous nanofibers. The proposed green bifunctional catalyst is easily recoverable and reusable for several consecutive cycles.

Synthesis of bifunctional receptor for fluoride and cadmium based on calix[4]arene with thiourea moieties

A new calix[4]arene thiourea derivative bearing a benzothiazolyl moiety (L) was synthetized and characterized by single crystal X-ray, NMR and ESI-TOF. The binding ability of the bifunctional receptor towards several ions was investigated in acetonitrile by means of UV–Visible and NMR spectroscopy. The UV–Vis studies of receptor L demonstrated a stoichiometry of 1:1 for all ions studied. Also, recognize selectively F− and Cd2+ with a detection limit of 97 and 37 μM, respectively.Also, 1H NMR titration of receptor L indicated that both thiourea bridge and phenolic hydroxyl functional groups played a critical role in the binding of F− and Cd2+ ions. 1H NMR spectrum showed that receptor L has a flattened-cone conformation in solution that changes to a cone conformation in the presence of fluoride while cadmium maintained the initial conformation.

Preparation and In Vitro Characterization of Dendrimer-based Contrast Agents for Magnetic Resonance Imaging.

Paramagnetic complexes of gadolinium(III) with acyclic or macrocyclic chelates are the most commonly used contrast agents (CAs) for magnetic resonance imaging (MRI). Their purpose is to enhance the relaxation rate of water protons in tissue, thus increasing the MR image contrast and the specificity of the MRI measurements. Current clinically approved contrast agents are low molecular weight molecules that are rapidly cleared from the body. The use of dendrimers as carriers of paramagnetic chelators can play an important role in the future development of more efficient MRI contrast agents. Specifically, the increase in local concentration of the paramagnetic species results in a higher signal contrast. Furthermore, this CA provides a longer tissue retention time due to its high molecular weight and size. Here, we demonstrate a convenient procedure for the preparation of macromolecular MRI contrast agents based on poly(amidoamine) (PAMAM) dendrimers with monomacrocyclic DOTA-type chelators (DOTA - 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate). The chelating unit was appended by exploiting the reactivity of the isothiocyanate (NCS) group towards the amine surface groups of the PAMAM dendrimer to form thiourea bridges. Dendrimeric products were purified and analyzed by means of nuclear magnetic resonance spectroscopy, mass spectrometry, and elemental analysis. Finally, high resolution MR images were recorded and the signal contrasts obtained from the prepared dendrimeric and the commercially available monomeric agents were compared.

Genetic Incorporation of a Reactive Isothiocyanate Group into Proteins.

Methods for the site-specific modification of proteins are useful for introducing biological probes into proteins and engineering proteins with novel activities. Herein, we genetically encode a novel noncanonical amino acid (ncAA) that contains an aryl isothiocyanate group which can form stable thiourea crosslinks with amines under mild conditions. We show that this ncAA (pNCSF) allows the selective conjugation of proteins to amine-containing molecular probes through formation of a thiourea bridge. pNCSF was also used to replace a native salt bridge in myoglobin with an intramolecular crosslink to a proximal Lys residue, leading to increased thermal stability. Finally, we show that pNCSF can form stable intermolecular crosslinks between two interacting proteins.

Genetic Incorporation of a Reactive Isothiocyanate Group into Proteins

AbstractMethods for the site‐specific modification of proteins are useful for introducing biological probes into proteins and engineering proteins with novel activities. Herein, we genetically encode a novel noncanonical amino acid (ncAA) that contains an aryl isothiocyanate group which can form stable thiourea crosslinks with amines under mild conditions. We show that this ncAA (pNCSF) allows the selective conjugation of proteins to amine‐containing molecular probes through formation of a thiourea bridge. pNCSF was also used to replace a native salt bridge in myoglobin with an intramolecular crosslink to a proximal Lys residue, leading to increased thermal stability. Finally, we show that pNCSF can form stable intermolecular crosslinks between two interacting proteins.

Design, synthesis, insecticidal activity, and structure-activity relationship (SAR): studies of novel triazone derivatives containing a urea bridge group based on transient receptor potential (TRP) channels.

Numerous compounds containing urea bridge and biurea moieties are used in a variety of fields, especially as drugs and pesticides. To search for novel, environmentally benign and ecologically safe pesticides with unique modes of action, four series of novel triazone analogues containing urea, thiourea, biurea, and thiobiurea bridge, respectively, were designed and synthesized, according to various calcium ion channel inhibitors which act on transient receptor potential protein. Their structures were characterized by [Formula: see text] NMR, [Formula: see text] NMR, and HRMS. The insecticidal activities of the new compounds were obtained. The bioassay results indicated that compounds containing a thiourea bridge and a thiobiurea bridge exhibited excellent insecticidal activities against bean aphid. Specifically, compounds [Formula: see text], [Formula: see text], and [Formula: see text] exhibited 85, 90, and 95% activities, respectively, at 10 mg/kg. Compounds [Formula: see text] (30%), [Formula: see text] (35%), [Formula: see text] (30%), and [Formula: see text] (40%) exhibited the approximate aphicidal activity of pymetrozine (30%) at 5 mg/kg. In addition, some target compounds exhibited insecticidal activities against lepidopteran pests. From a molecular design standpoint, the information obtained in this study could help in the further design of new derivatives with improved insecticidal activities.

Cyclic Enkephalins with a Diversely Substituted Guanidine Bridge or a Thiourea Bridge: Synthesis, Biological and Structural Evaluations

Two series of 22 and 15 atom cyclic enkephalins incorporating a diversely substituted guanidine bridge have been prepared to assess the potential effect of the bridge substitutions on their opioid activity profile. The most notable results were obtained with the shortest cyclic analogues, which showed a significant variation of their binding affinity toward μ and δ opioid receptors in relation to bridge substitution. NMR studies were performed to rationalize these data. Some small analogues were found to exist as at least one major and one minor stable forms, which could be separated by chromatography. In particular, the compounds 13 and 14 with a cyclic substituent were separated in three isomers and the basis of this multiplicity was explored by 2D NMR spectroscopy. All compounds were agonists with slight selectivity for the μ opioid receptor. Compounds 7a (thiourea bridge) and 10a (N-Me-guanidine bridge) showed nanomolar affinity toward μ receptor, the latter being the more selective for this receptor (40-fold).

Mononuclear Ferrocenophane Structural Motifs with Two Thiourea Arms Acting as a Dual Binding Site for Anions and Cations

The synthesis of a new type of mononuclear ferrocenophane-based thiourea, in which the ferrocene moiety is simultaneously attached to two thiourea groups directly from 1,1'-bis(isothiocyanato)ferrocene, is reported. These nitrogen-rich structural motifs show remarkable ion-sensing properties because of the presence of the redox active ferrocene unit and the thiourea bridges, which unexpectedly act as a dual binding site for anions and metal ions. They display a selective downfield shift of the thiourea protons and a remarkable cathodic shift of the ferrocene/ferrocenium redox couple with F(-), AcO(-), H(2)PO(4)(-), and HP(2)O(7)(3-) anions, whereas the selective recognition of Hg(2+) metal cations is achieved either by electrochemical or by spectral measurements. The preferred binding modes are proposed for the most representative complexes by means of density functional theory based theoretical calculations showing the Janus-like faces of the receptor.

5-tert-Butyl-1-[2-(2,4-dichlorophenoxy)propionyl]thiobiuret

The title compound, C15H19Cl2N3O3S, is a phenoxythiourea compound with a tert-butylaminocarbonyl group attached to the distal N atom of the thiourea bridge. There are intramolecular N—H...O and N—H...S hydrogen bonds, forming six- and five-membered rings.

Relaxometric and solution NMR structural studies on ditopic lanthanide(iii) complexes of a phosphinate analogue of DOTA with a fast rate of water exchange

A novel "ditopic" ligand containing two monophosphinate triacetate DOTA-like units linked by a thiourea bridge has been synthesized and its complexes with Ln3+ ions (Ln = Y, Eu, Gd, Dy) investigated by NMR spectroscopy and relaxometry. The presence of one water molecule in the first coordination sphere has been determined by the measurement of the dysprosium(III)-induced 17O NMR shifts. The 1H and 31P NMR spectra of the Eu(III) derivative indicate a higher abundance of the fast-exchanging twisted square antiprismatic (m) isomer than the isomeric square antiprismatic (M; m/M = 3:2) complex. The analysis of the 89Y and 13C T1 NMR relaxation times in the Gd(III)/Y(III) mixed complex have provided useful structural information. Values of ca. 6.3 and 8.2 A for the Gd...Y and Gd...C distances, respectively, have been estimated which indicate a rather compact solution structure. This result finds support in the value of the relaxivity whose increase (at 20 MHz and 298 K) on passing from the monomeric (5.7 s(-1) mM(-1)) to the ditopic complex (8.2 s(-1) mM(-1)) can be attributed to the doubling of the inner-sphere term following the doubling of the molecular size. The structural and dynamic relaxivity-controlling parameters were assessed by a simultaneous fitting of the variable temperature 17O NMR and 1H NMRD relaxometric data. The mean water residence lifetime (298tauM) has been found to be 53 ns, one of the shortest values reported for ditopic complexes. The reorientational correlation time is two times longer (298tauR = 183 ps) than the corresponding value of the parent monomeric Gd(III) complex, thus supporting the view of a limited degree of internal rotation. The possible influence of magnetic Gd-Gd coupling has been excluded by a comparison of the 1H NMRD profiles of the homodinuclear Gd(III)/Gd(III) and the heterodinuclear Gd(III)/Y(III) complexes.

D-Ribofuranosylenamine: a versatile starting material for preparing azasugar thioglycosides and building blocks for thioureylene-di-nucleosides

Six-membered azasugar thioglycosides (piperidines) are prepared from a β- d-ribofuranosylenamine, with a 1,5-anhydro derivative being the key intermediate. The α-anomer of the same d-ribofuranosylenamine is transformed into a 5-deoxy-5-isothiocyanato derivative, useful for preparing d-ribosylamino derivatives with a non-ionic thiourea bridge, isosteric of the phosphate bridge. The prepared thioureas are potential building blocks for the synthesis of thioureylene-di-nucleosides.

A general entry to linear, dendritic and branched thiourea-linked glycooligomers as new motifs for phosphate ester recognition in water.

A blockwise iterative synthetic strategy for the preparation of linear, dendritic and branched full-carbohydrate architectures has been developed by using sugar azido(carbamate) isothiocyanates as key templates; the presence of intersaccharide thiourea bridges provides anchoring points for hydrogen bond-directed molecular recognition of phosphate esters in water.

Synthesis and crystal structures of urea and thiourea derivatives of diruthenium(II,III) tetraacetate

Diadduct complexes of the mixed-valent form of diruthenium tetraacetate, [Ru 2(μ-O 2CCH 3) 4L 2](PF 6), with L=urea ( 1), 1,1,3,3-tetramethylurea (tmu) ( 2) and 1,1,3,3-tetramethyl-2-thiourea (tmtu) ( 3) have been synthesized and characterized by elemental analysis, IR and UV–Vis spectroscopy, magnetic susceptibility, cyclic voltammetry and X-ray crystallography. Compound 1 crystallizes as a co-diadduct system from 1-propanol in which both [Ru 2(μ-O 2CCH 3) 4(urea) 2] + and [Ru 2(μ-O 2CCH 3) 4(1-propanol) 2] + cations are present in the unit cell. Complex 3 displays a very long RuS bond of 2.610(2) Å and is only the second example of a sulfur-donor adduct of a diruthenium tetracarboxylate that has been structurally characterized. Electrochemical measurements on 2 and 3 show them to have reduction potentials of −487 and −541 mV (vs. Fc/Fc +), respectively, which is in the range of moderate to strong axial donor adducts despite the long RuS bond in 3. Reaction of [Ru 2(μ-O 2CCH 3) 4(H 2O) 2](PF 6) with thiourea yields a 1:1 complex, [Ru 2(μ-O 2CCH 3) 4(thiourea)](PF 6), which from solubility and infrared evidence appears to be a polymer in which the thiourea bridges through the sulfur and one of the amine nitrogens.

Conformational energetics of sugar thioureas and synthesis of glycosyl thioureido sugars

The rate and outcome of the reaction of 6-deoxy-6-isothiocyanatoaldopyranoside derivatives with ammonia depend strongly on the nature of the hydroxyl protecting groups and solvent. In pyridine as solvent, the expected thioureas are obtained as the sole reaction products. A marked preference for the E configuration at the sugarNHC(S) bond is observed for silylated as compared to acetylated derivatives. Rotational barrier calculations, temperature-induced NH shifts, and other NMR data indicate a strict relationship between the E rotamer population and the existence of an intramolecular NH…O-5 hydrogen bond that fits a pseudo γ-turn. Competition between inter- and intra-molecular hydrogen bonding rather than steric factors probably explain these results. Acetal and trimethylsilyl ether derivatives have been further used in the preparation of fully unprotected derivatives. The procedure has been extended to the first synthesis of (1→6)-linked glycosyl phosphosugar analogues incorporating thiourea bridges as phosphate surrogates.

Thiourea analogues of resiniferatoxin as ligands for the vanilloid receptor

A thiourea bridge was tested as a linker to replace the OC(O)CH 2 ester group that connects resiniferonol-9,13,14-orthophenylacetate to the 3-methoxy-4-hydroxyphenyl moiety in resiniferatoxin (RTX). The resulting compounds showed lower affinity for the vanilloid receptor than did the parent RTX.

ChemInform Abstract: Synthesis of Acylated Thioureylenedisaccharides.

Thioureylenedisaccharides have been prepared from sugar isothiocyanates and aminosugars. Thus, a thiourea bridge connects the (C-1)–(C-2) or (C-2)–(C-2) positions of some pentose, hexose, and heptose frameworks with different anomeric patterns in compounds (16)–(28). With this aim, several C-2-functionalised derivatives of compound (7) have been synthesized. A (Z,Z)-conformation is proposed for thioureylenedisaccharides in solution.

Synthesis of acylated thioureylenedisaccharides

Thioureylenedisaccharides have been prepared from sugar isothiocyanates and aminosugars. Thus, a thiourea bridge connects the (C-1)–(C-2) or (C-2)–(C-2) positions of some pentose, hexose, and heptose frameworks with different anomeric patterns in compounds (16)–(28). With this aim, several C-2-functionalised derivatives of compound (7) have been synthesized. A (Z,Z)-conformation is proposed for thioureylenedisaccharides in solution.

ChemInform Abstract: MELANOTROPIN RECEPTORS. II. SYNTHESIS AND BIOLOGICAL ACTIVITY OF α‐MELANOTROPIN/TOBACCO MOSAIC VIRUS DISULFIDE CONJUGATES

AbstractAsymm. Disulfid‐Konjugate von Mercaptosuccinyl‐Tabakmosaikvirus (TMV∼SH) mit dem α‐Melanotropin (Ia) (α‐MSH‐Analogen (Id) werden über das S‐Sulfoderivat (Ic) [zugänglich aus (Ib)] dargestellt.