- The thermal sigmatropic isomerization of pseudosaccharyl crotyl ether
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The thermally induced sigmatropic isomerization of the pseudosaccharyl crotyl ether, 3-(E)-but-2- enoxy)-1,2-benzisothiazole 1,1-dioxide (CBID), has been investigated by using temperature dependent infrared spectroscopy, differential scanning calorimetry (DSC), and polarized light thermomicroscopy. The reaction can take place in both melted and crystalline phases, affording the product resulting from the [3,3′] migration of the allylic system from O to N, 2-(E)-1-methylprop-2-en-1,2-benzisothiazol-3(2H)- one 1,1-dioxide (CBIOD). In the melt, the activation energy of the process was determined as being 49.1±5.3 kJ mol-1, with k=(22.2±0.6)×10 4 s-1 at 140 °C. In the solid state, at 110 °C, the rate constant drops by one order of magnitude [k=(1.46±0.07) ×104 s-1]. The enthalpy of reaction, determined by DSC, isΔrxH=-27.0±0.8 kJ mol-1. Assignments were proposed for the infrared spectra of the observed neat condensed phases of the two compounds.
- Cabral,Maria,Martelo,Eusébio,Cristiano,Fausto
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- Synthesis, Structure, and Cytotoxicity of a New Sulphanyl-Bridged Thiadiazolyl-Saccharinate Conjugate: The Relevance of S???N Interaction
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Reports showing that the copper concentration is considerably higher in neoplasms than in normal tissues prompted the need to develop selective copper chelators. We disclosed recently that some N-linked tetrazole-saccharinates bind selectively to copper, forming complexes that are highly cytotoxic towards cancer cells. Because tetrazole-saccharinates are photolabile, due to the photoreactivity of tetrazoles, we proposed thiadiazolyl-saccharinates as an alternative. Herein we describe the synthesis, structure, and monomeric photochemistry of a sulphanyl-bridged thiadiazolyl-saccharinate, 3-[(5-methyl-1,3,4-thiadiazol-2-yl)sulphanyl]-1,2-benzothiazole 1,1-dioxide (MTSB). The monomeric structure, charge density analysis, and characteristic infrared spectrum of MTSB were investigated theoretically, using quantum chemical calculations, and also experimentally, using matrix-isolation infrared spectroscopy. The crystal structure was investigated by combining X-ray crystallography with infrared and Raman spectroscopies. Results show that the structure of isolated MTSB is similar to that found in the crystal, with an S???N interaction clearly contributing to the structure of the molecule and of the crystal. Matrix irradiation revealed a high photostability of MTSB, compared to parent tetrazole-saccharinates and to the 5-methyl-1,3,4-thiadiazole building block, emphasizing the photostabilizing effect of the saccharyl system. Finally, in vitro toxicity assays of MTSB showed a copper concentration-dependent toxicity against cancer cells, without affecting normal cells. In particular, MTSB was most effective towards the hepatic (HepG2), neuroblastoma (SH-SY5), and lymphoma cell lines (U937). Thus, MTSB represents a promising lead for cancer chemotherapy based on chelating agents.
- Cabral, Lília I. L.,Brás, Elisa M.,Henriques, Marta S. C.,Marques, Catia,Frija, Luís M. T.,Barreira, Luísa,Paix?o, José António,Fausto, Rui,Cristiano, Maria Lurdes S.
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- Structure and photochemistry of a saccharyl thiotetrazole
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The molecular structure and photochemistry of 5-thiosaccharyl-1-methyltetrazole (TSMT) were studied by means of matrix-isolation FTIR spectroscopy, X-ray crystallography, and theoretical calculations. The calculations predicted two conformers of TSMT that differ in energy by more than 15 kJ mol-1. The infrared spectrum of TSMT isolated in solid argon was fully assigned on the basis of the spectrum calculated (O3LYP/6-311++G(3df,3pd)) for the most stable conformer. In the crystal, TSMT molecules were found to assume the same conformation as for the isolated molecule, with each molecule forming four hydrogen bonds with three neighboring molecules, leading to a network of TSMT oligomers. Upon UV (λ = 265 nm) irradiation of the matrix-isolated TSMT, two photodegradation pathways were observed, both arising from cleavage of the tetrazolyl ring. Pathway a involves cleavage of the N1-N2 and N3-N4 bonds with extrusion of N2, leading to photostable diazirine and thiocarbodiimide derivatives. The photostability of the photoproduced diazirine under the conditions used precluded its rearrangement to the nitrile imine, as reported for 5-phenyltetrazole by Bégué et al. (J. Am. Chem. Soc. 2012, 134, 5339). Pathway b involves cleavage of the C5-N1 and N4-N3 bonds, leading to a thiocyanate and methyl azide, the latter undergoing subsequent fragmentation to give CNH.
- Ismael,Borba,Henriques,Paix?o,Fausto,Cristiano
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- On the development of selective chelators for cadmium: Synthesis, structure and chelating properties of 3-((5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)amino)benzo [d]isothiazole 1,1-dioxide, a novel thiadiazolyl saccharinate
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Aquatic contamination by heavy metals is a major concern for the serious negative con-sequences it has for plants, animals, and humans. Among the most toxic metals, Cd(II) stands out since selective and truly efficient methodologies for its removal are not known. We report a novel multidentate chelating agent comprising the heterocycles thiadiazole and benzisothiazole. 3-((5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)amino)benzo[d]isothiazole 1,1-dioxide (AL14) was syn-thesized from cheap saccharin and characterized by different techniques, including single crystal X-ray crystallography. Our studies revealed the efficiency and selectivity of AL14 for the chelation of dissolved Cd(II) (as compared to Cu(II) and Fe(II)). Different spectral changes were observed upon the addition of Cd(II) and Cu(II) during UV-Vis titrations, suggesting different complexation interactions with both metals.
- Amado, Patrícia S. M.,Barreira, Luísa,Cristiano, Maria L. S.,Fernandes, André L.,Guerreiro, Bruno,Leal, Joana F.,Paix?o, José A.
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- Synthesis, characterization and antimicrobial evaluation of new 3-(Alkyl/Arylamino)benzo[d]isothiazole 1,1-derivatives
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The saccharine nucleus has long been recognized as a significant component in medicine. A series of pseudo-saccharine amines derivatives (7a-j) were synthesized and examined for their antibacterial activity. After testing all compounds, 7b, 7f, 7g, 7i and 7j were found most effective against Escherichia coli, Streptococcus aureus and Bacillus subtilis strains. The MIC of the compound was found from 4.6 to 16.1 μM. Further, compound 7f and 7i exhibited excellent activity against E.coli and Bacillus subtilis with MIC value 4.6 and 4.7 μM respectively. The compound 7b and 7i was found active against all the three bacteria. The zone inhibition was observed at 10 μM against Escherichia coli, Staphylococcus aureus and Bacillus subtilis at 0.9, 1.8, 3.9 respectively for 7b and 1.0, 1.8 and 2.0 cm respectively for 7i.
- Kamble, Dhanraj P.,Shankarwar, Anil G.,Mane, Yogesh D.,Tigote, Radhakrishna M.,Sarnikar, Yuvaraj P.,Madje, Balaji R.
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p. 797 - 804
(2021/09/08)
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- Discovery of a Potent and Orally Bioavailable Hypoxia-Inducible Factor 2α (HIF-2α) Agonist and Its Synergistic Therapy with Prolyl Hydroxylase Inhibitors for the Treatment of Renal Anemia
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Activation of hypoxia-inducible factor 2 (HIF-2) has emerged as a potent renal anemia treatment strategy. Here, the benzisothiazole derivative 26 was discovered as a novel HIF-2α agonist, which first demonstrated nanomolar activity (EC50 = 490 nM, Emax = 349.2%) in the luciferase reporter gene assay. Molecular dynamics simulations indicated that 26 could allosterically enhance HIF-2 dimerization. Furthermore, compound 26 had a good pharmacokinetic profile (the oral bioavailability in rats was 41.38%) and an in vivo safety profile (the LD50 in mice was greater than 708 mg·kg-1). In the in vivo efficacy assays, the combination of 26 and the prolyl hydroxylase inhibitor, AKB-6548, was confirmed for the first time to synergistically increase the plasma erythropoietin level in mice (from 260 to 2296 pg·mL-1) and alleviate zebrafish anemia induced by doxorubicin. These results provide new insights for HIF-2α agonists and the treatment of renal anemia.
- Yu, Yancheng,Yang, Fulai,Yu, Quanwei,Liu, Simeng,Wu, Chenyang,Su, Kaijun,Yang, Le,Bao, Xiaoqian,Li, Zhihong,Li, Xiang,Zhang, Xiaojin
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p. 17384 - 17402
(2021/11/16)
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- Insight into the binding mode of HIF-2 agonists through molecular dynamic simulations and biological validation
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Hypoxia-inducible factor-2 (HIF-2), a heterodimeric transcriptional protein consisting of HIF-2α and aryl hydrocarbon receptor nuclear translocator (ARNT) subunits, has a broad transcriptional profile that plays a vital role in human oxygen metabolism. M1001, a HIF-2 agonist identified by high-throughput screening (HTS), is capable of altering the conformation of Tyr281 of the HIF-2α PAS-B domain and enhancing the affinity of HIF-2α and ARNT for transcriptional activation. M1002, an analog of M1001, shows improved efficacy than M1001. However, the cocrystal structure of M1001 and HIF-2 has some defects in revealing the agonist binding mode due to the relatively low resolution, while the binding mode of M1002 remained unexplored. To in-depth understand agonist binding profiles, herein, the molecular dynamic (MD) simulations was applied to construct a stable agonist-protein model, and a possible binding mode was proposed through the analysis of the binding free energy and hydrogen bonding of the simulation results. Nine compounds were then synthesized and evaluated to verify the proposed binding mode. Among them, compound 10 manifested improved agonistic activity and reduced toxicity compared to M1002. This study provides deep insight into the binding mode of such HIF-2 agonists, which would be useful for designing novel agonists for HIF-2.
- Yu, Yancheng,Yu, Quanwei,Liu, Simeng,Wu, Chenyang,Zhang, Xiaojin
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- Design, synthesis and in silico insights of new 7,8-disubstituted-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives with potent anticancer and multi-kinase inhibitory activities
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Aiming to obtain an efficient anti-proliferative activity, structure- and ligand-based drug design approaches were expanded and utilized to design and refine a small compound library. Subsequently, thirty-two 7,8-disubstituted-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives were selected for synthesis based on the characteristic pharmacophoric features required for PI3K and B-Raf oncogenes inhibition. All the synthesized compounds were evaluated for their in vitro anticancer activity. Compounds 17 and 22c displayed an acceptable potent activity according to the DTP-NCI and were further evaluated in the NCI five doses assay. To validate our design, compounds with the highest mean growth inhibition percent were screened against the target PI3Kα and B-RafV600E to confirm their multi-kinase activity. The tested compounds showed promising multi-kinase activity. Compounds 17 and 22c anticancer effectiveness and multi-kinase activity against PI3Kα and B-RafV600E were consolidated by the inhibition of B-RafWT, EGFR and VEGFR-2 with IC50 in the sub-micromolar range. Further investigations on the most potent compounds 17 and 22c were carried out by studying their safety on normal cell line, in silico profiling and predicted ADME characteristics.
- Abdel Gawad, Nagwa M.,El Kerdawy, Ahmed M.,George, Riham F.,Georgey, Hanan H.,Mohamed, Abdalla R.
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- Versatile new reagent for nitrosation under mild conditions
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Here we report a new chemical reagent for transnitrosation under mild experimental conditions. This new reagent is stable to air and moisture across a broad range of temperatures and is effective for transnitrosation in multiple solvents. Compared with traditional nitrosation methods, our reagent shows high functional group tolerance for substrates that are susceptible to oxidation or reversible transnitrosation. Several challenging nitroso compounds are accessed here for the first time, including 15N isotopologues. X-ray data confirm that two rotational isomers of the reagent are configurationally stable at room temperature, although only one isomer is effective for transnitrosation. Computational analysis describes the energetics of rotamer interconversion, including interesting geometry-dependent hybridization effects.
- Galloway, Jordan D.,Sarabia, Cristian,Fettinger, James C.,Hratchian, Hrant P.,Baxter, Ryan D.
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supporting information
p. 3253 - 3258
(2021/05/06)
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- Preparation method and medical application of benzisothiazole and benzothiophene
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The invention discloses a preparation method and medical application of benzisothiazole and benzothiophene, and telates to the field of pharmaceutical chemistry. According to the invention, benzisothiazole and benzothiophene are the first type of HIF-2 agonists; compared with a compound M1001 found by the applicant in the earlier stage, the invention has better HIF-2 agonist activity, and has remarkable enhancement activity on expression of mRNA and protein of EPO, VGEF, Glut1, NDRG1 and the like at the downstream of HIF-2, so that the invention can be used for preparing drugs for treating and/or preventing chronic kidney diseases/chronic renal anemia, dyslipidemia and high cholesterol caused by abnormal expression of HIF-2; and the method has a good industrialization prospect.
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Paragraph 0098; 0102
(2021/08/19)
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- NITROSATION REAGENTS AND METHODS
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Provided are compounds that can find use as nitrosation reagents. Provided are nitrosation methods that include reacting a substrate with one of the provided nitrosation reagents and thereby generating a nitrosation product. Provided are kits including a nitrosation reagent. Provided are compositions wherein the nitrosation reagent is enriched in the 15N isotope.
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Paragraph 00152-00154; 00169-00172
(2022/02/06)
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- Pyridinyl Amide Ion Pairs as Lewis Base Organocatalysts
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Pyridinyl amide ion pairs carrying various electron-withdrawing substituents were synthesized with selected ammonium or phosphonium counterions. Compared to neutral pyridine-based organocatalysts, these new ion pair Lewis bases display superior catalytic
- Amp?ler, Torsten,Helberg, Julian,Zipse, Hendrik
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p. 5390 - 5402
(2020/05/19)
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- Synthesis and antileishmanial activity of 1,2,4,5-tetraoxanes against leishmania donovani
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A chemically diverse range of novel tetraoxanes was synthesized and evaluated in vitro against intramacrophage amastigote forms of Leishmania donovani. All 15 tested tetraoxanes displayed activity, with IC50 values ranging from 2 to 45 μm. The most active tetraoxane, compound LC140, exhibited an IC50 value of 2.52 ± 0.65 μm on L. donovani intramacrophage amastigotes, with a selectivity index of 13.5. This compound reduced the liver parasite burden of L. donovani-infected mice by 37% after an intraperitoneal treatment at 10 mg/kg/day for five consecutive days, whereas miltefosine, an antileishmanial drug in use, reduced it by 66%. These results provide a relevant basis for the development of further tetraoxanes as effective, safe, and cheap drugs against leishmaniasis.
- Cabral, Lília I.L.,Pomel, Sébastien,Cojean, Sandrine,Amado, Patrícia S.M.,Loiseau, Philippe M.,Cristiano, Maria L.S.
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supporting information
(2020/02/11)
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- Solvent-free oxidation of benzyl alcohols catalysed by a tetrazole-saccharinate Zn(II) complex under microwave radiation: The role of the ligand and the reaction mechanism
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Herein we present an efficient methodology for the microwave-assisted peroxidative oxidation of benzyl alcohols to the corresponding aldehydes by using a novel and stable tetrazole-saccharinate zinc(II) catalyst, along with some insights into the reaction mechanism. This methodology is distinguished by the use of easily available and cheap reagents on the genesis of the zinc catalyst, mild reaction conditions, very short reaction periods (5–20 min) and no need to add an organic solvent. Furthermore, the use of TBHP (70percent. aq.) as oxidizing agent turn this protocol a convenient one for benzyl alcohol oxidation in yields up to 98percent.
- Cristiano, M. Lurdes S.,Fernandes, André L.,Frija, Luís M. T.,Pombeiro, Armando J. L.
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- NEW ENDOPEROXIDE COMPOUNDS, PROCESS FOR OBTAINING THEM AND USES THEREOF FOR CONTROL OF PERKINSIOSIS IN BIVALVES
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The present invention relates to new endoperoxide compounds and compositions, and to a process for producing them for prophylaxis and control of perkinsiosis in bivalves. Endoperoxide compounds with biological activity against Perkinsus olseni include 13
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Page/Page column 21
(2020/12/11)
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- Preparation method of probenazole
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The invention provides a preparation method of probenazole. The method comprises the following steps: by taking saccharin as an initial raw material, chlorinating with thionyl chloride in 1, 4-dioxaneto obtain a chloride, adding a high-boiling-point solvent to remove the solvent dioxane and excessive thionyl chloride, directly carrying out substitution reaction with a sodium salt or a potassium salt of allyl alcohol, and carrying out centrifugal desalination and cooling recrystallization to directly obtain high-purity probenazole. The preparation method is capable of solveing the problem of difficult kettle rotation caused by chloride solidification in the prior art, avoiding the generation of allyl chloride during etherification by allyl alcohol, and reducing the water washing procedurein the traditional method. Compared with the traditional method, the advantages are that the preparation method is simple and convenient to operate, high in yield, less in three wastes and high in purity of the obtained product, greatly saves the production cost and the environmental protection cost, and is easy to realize industrialization.
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Paragraph 0005; 0031-0036; 0041-0046
(2020/02/10)
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- Sulfenyl Ynamides in Gold Catalysis: Synthesis of Oxo-functionalised 4-aminoimidazolyl Fused Compounds by Intermolecular Annulation Reactions
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Functionalised N-heterocyclic pyridinium N-aminides have been designed and synthesised to evaluate a nitrenoid-based annulation strategy into imidazole-fused oxo-substituted frameworks of importance to medicinal and agrochemical discovery programmes. Sulfenyl substituted ynamides were identified as privileged reactants affording productive gold-catalysed annulation reactions with these and other nitrenoids. This annulation method provides selective and efficient access into geminally amino-sulfenyl substituted nitrogen heterocycles under mild reaction conditions. (Figure presented.).
- Arce, Elsa M.,Lamont, Scott G.,Davies, Paul W.
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supporting information
p. 2503 - 2509
(2020/04/30)
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- INHIBITORS OF THE YAP/TAZ-TEAD INTERACTION AND THEIR USE IN THE TREATMENT OF CANCER
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The invention relates to compounds of formula (I): wherein R1; R2, R3, R4, R5 and are as defined in the description. The compounds of formula (I) are inhibitors of the YAP/TAZ-TEAD interaction and thu
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Paragraph 0080
(2020/04/21)
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- Application of compound in RADNOVA anti-radiation treatment
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The invention relates to the field of biological medicines, in particular to application of a compound RADNOVA in preparation of anti-radiation medicines. The application has the beneficial effects that the new application of the compound RADNOVA in radia
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Paragraph 0032
(2020/07/02)
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- Application for compound RADNOVA in treatment of enteritis
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The invention relates to the field of biological medicines, specifically to an application of a compound RADNOVA in preparation of a medicine used for treatment of inflammatory bowel diseases. The compound RADNOVA provided by the invention has the followi
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Paragraph 0014; 0021-0022
(2020/07/15)
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- Novel compounds that are inhibitors of YAP/TAZ-TEAD interaction and their use in the treatment of malignant mesothelioma
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These compounds are useful as inhibitors of the YAP/TAZ-TEAD interaction.
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Paragraph 0384-0386
(2020/02/01)
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- In vitro assessment of antimicrobial, antioxidant, and cytotoxic properties of saccharin–tetrazolyl and –thiadiazolyl derivatives: The simple dependence of the ph value on antimicrobial activity
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The antimicrobial, antioxidant, and cytotoxic activities of a series of saccharin–tetrazolyl and –thiadiazolyl analogs were examined. The assessment of the antimicrobial properties of the referred-to molecules was completed through an evaluation of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values against Gram-positive and Gram-negative bacteria and yeasts. Scrutiny of the MIC and MBC values of the compounds at pH 4.0, 7.0, and 9.0 against four Gram-positive strains revealed high values for both the MIC and MBC at pH 4.0 (ranging from 0.98 to 125 μg/mL) and moderate values at pH 7.0 and 9.0, exposing strong antimicrobial activities in an acidic medium. An antioxidant activity analysis of the molecules was performed by using the DPPH (2,2-diphenyl-1-picrylhydrazyl) method, which showed high activity for the TSMT (N-(1-methyl-2H-tetrazol-5-yl)-N-(1,1-dioxo-1,2-benzisothiazol-3-yl) amine, 7) derivative (90.29% compared to a butylated hydroxytoluene positive control of 61.96%). Besides, the general toxicity of the saccharin analogs was evaluated in an Artemia salina model, which displayed insignificant toxicity values. In turn, upon an assessment of cell viability, all of the compounds were found to be nontoxic in range concentrations of 0–100 μg/mL in H7PX glioma cells. The tested molecules have inspiring antimicrobial and antioxidant properties that represent potential core structures in the design of new drugs for the treatment of infectious diseases.
- Frija, Luís M. T.,Ntungwe, Epole,Sitarek, Przemys?aw,Andrade, Joana M.,Toma, Monika,?liwiński, Tomasz,Cabral, Lília,Cristiano, M. Lurdes S.,Rijo, Patrícia,Pombeiro, Armando J. L.
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- Substituted benzisothiazole compound and application
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The invention discloses a substituted benzisothiazole compound. R1 is cyan, hydroxyl, C1-C4 alkyl, cyclopropyl, cyanomethyl, methoxyl, ethyoxyl, acetyl, trifluoroacetyl, C1-C4 alkoxycarbonyl and methylsulfonyl or ethylsulfonyl, R2 is independently selected from hydrogen, halogen, cyan, methyl, methoxyl, trifluoromethyl and trifluoromethoxyl or difluoromethoxyl, n is 1, 2, 3 or 4, m is 1 or 2, and J is replaced thiazole, isothiazole or pyridine. The compound has excellent activity and good plant tolerance and environmental safety under low concentration and can inhibit or destroy various pathogenic fungi and bacteria generated by plants or soil and kill various insect pests and mites, and sterilization and insecticidal spectrums of the compound are widened. According to the preparation method, used raw materials are economical and easy to get, and the preparation method is high in yield and low in synthesis process cost and has good sterilization activity and pest and mite killing activity.
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Paragraph 0148; 0150; 0151; 0152; 0230; 0232-0234
(2018/03/24)
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- NEW COMPOUNDS INHIBITORS OF THE YAP/TAZ-TEAD INTERACTION AND THEIR USE IN THE TREATMENT OF MALIGNANT MESOTHELIOMA
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The invention relates to compounds of formula (I) wherein R1, R2, R3, R4, R5 and R6 are as defined in the description. The compounds of formula (I) are inhibitors of the YAP/TAZ-TEAD intera
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Page/Page column 15
(2017/05/02)
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- Saccharin Aza Bioisosteres - Synthesis and Preclinical Property Comparisons
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Saccharin is a well-known scaffold in drug discovery. Herein, we report the synthesis and preclinical property comparisons of three bioisosteres of saccharin: aza-pseudosaccharins (cluster B), and two new types of aza-saccharins (clusters C and D). We dem
- Chen, Yantao,Aurell, Carl-Johan,Pettersen, Anna,Lewis, Richard J.,Hayes, Martin A.,Lepist?, Matti,Jonson, Anna C.,Leek, Hanna,Thunberg, Linda
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supporting information
p. 672 - 677
(2017/06/13)
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- Copper(II) and cobalt(II) tetrazole-saccharinate complexes as effective catalysts for oxidation of secondary alcohols
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Mononuclear Cu(II) and Co(II) complexes comprising 2-methyltetrazole-saccharinate bidentate N,N-chelating ligand have been synthesized for the first time and tested as homogeneous catalysts for oxidation of secondary alcohols in a solvent-free and microwave assisted protocol using aqueous tert-butyl hydroperoxide (TBHP) as oxidant. The developed catalytic system exhibits broad functional group compatibility, allowing efficient and selective conversion of a variety of secondary alcohols, including allylic ones, into the corresponding ketones. With typical 0.2 mol% content of the catalyst and under 20–50 W microwave irradiation, most reactions are complete within 10 min, presenting TONs up to 5.5 × 102 and TOFs up to 1.1 × 104 h?1. No additives and co-oxidants have been used, while TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxyl) acts as inhibitor in most cases. A plausible reaction mechanism involving the new catalytic systems is outlined.
- Frija, Luís M.T.,Alegria, Elisabete C.B.A.,Sutradhar, Manas,Cristiano, M. Lurdes S.,Ismael, Amin,Kopylovich, Maximilian N.,Pombeiro, Armando J.L.
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p. 283 - 290
(2016/11/04)
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- THIOXOTHIAZOLIDINE DERIVATIVE HAVING RAS FUNCTION INHIBITORY EFFECT
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The present invention provides an anticancer drug having a Ras function inhibitory action. The present invention provides a Ras function inhibitor comprising a compound represented by the formula (I′): wherein each symbol is as defined in the present spec
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Paragraph 0755; 0756
(2014/07/22)
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- Structure-based design and synthesis of novel pseudosaccharine derivatives as antiproliferative agents and kinase inhibitors
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This study is concerned with the implementation of structure-based techniques for the design of new heterocyclic compounds based on pseudosaccharine scaffold with protein kinase inhibition activity. This nucleus was exploited based on the well-known quinazoline core and its interactions with several protein kinases. Two series of compounds employing this new scaffold were synthesized and evaluated at enzymatic and cellular levels. Compound 9b displayed broad spectrum antiproliferative activity on NCI 60-cell lines panel with mean GI50 of 5.4 μM. Investigation of the molecular mechanism showed probable inhibitory activity against Src kinase.
- Elsayed, Mohamed S.A.,El-Araby, Moustafa E.,Serya, Rabah A.T.,El-Khatib, Ahmed H.,Linscheid, Michael W.,Abouzid, Khaled A.M.
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p. 122 - 131
(2013/04/23)
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- Molecular structure of nitrogen-linked methyltetrazole-saccharinates
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The molecular structures of nitrogen-linked 1- and 2-methyltetrazole- saccharinates, were investigated in the crystalline phase using X-ray crystallography and infrared and Raman spectroscopies, complemented by quantum chemical calculations performed at the DFT(B3LYP)/6-31++G(d,p) level of theory for the isolated molecules. In the neat crystalline solid (space group P1?, a = 6.9763 ?, b = 8.3097 ?, c = 10.0737 ?, α = 96.517°, β = 107.543°, γ = 99.989°; Z = 2), 1-methyltetrazole-saccharinate units assume the most stable configuration for the isolated molecule, (1H)-1-methytetrazole iminosaccharin tautomeric form (1MTIS), with the NC spacer linking the two heterocycles. On the other hand, neat crystalline 2-methyl derivative units (space group P1?, a = 7.8010 ?, b = 8.6724 ?, c = 9.4984 ?, α = 114.083°, β = 107.823°, γ = 93.080°; Z = 2) exist in the (2H)-2-methytetrazole aminosaccharin tautomeric form (2MTAS), with the two heterocycles connected by an NH spacer. In both crystals, the structure consists of a packing of dimeric units, the dimers formed via hydrogen bonding involving either the NH group of the saccharyl system (1MTIS) or the spacer amine group (2MTAS). In the former, the hydrogen bond is bifurcated and the NH group acts as a donor both towards a neighbor molecule and an N atom of the tetrazole ring, forming an intramolecular hydrogen bond. The observed difference in the crystallographic basic units of the two compounds reveals the prevalence of the H-bond networks in determining the structural preferences of the tetrazole-saccharinates in the solid state. Such structural flexibility appears also to be of potential interest in the design of new ligands based on the tetrazole-saccharinate framework. The relative strengths of the H-bonds in the crystals of the two compounds were evaluated through inspection of their vibrational spectra and empirical correlations between spectroscopic data and the H-bond enthalpies and distances.
- Ismael, Amin,Paix?o, José António,Fausto, Rui,Cristiano, Maria Lurdes S.
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experimental part
p. 128 - 142
(2012/10/08)
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- Structure and photochemistry of a novel tetrazole-saccharyl conjugate isolated in solid argon
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A combined matrix isolation FTIR and theoretical DFT/B3LYP/6-311++G(3df, 3pd) study of the novel synthesised tetrazole-saccharyl conjugate 2-[1-(1H-tetrazol-5-yl)ethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide [1-TE-BZT] was performed. In the gas phase, at room temperature, the compound exists as a mixture of six isomeric forms (four conformers of 1H tautomer and two conformers of 2H tautomer). According to theoretical calculations, conformers 1H were the most stable and the relative energies among the three most stable forms are lower than 4 kJ mol-1. These conformers benefit from stabilising intramolecular hydrogen bonds-like interactions involving the 1H of the tetrazole ring and the carbonyl oxygen of the saccharyl moiety. The photochemistry of 1-TE-BZT in solid argon was investigated and theoretical DFT/B3LYP/6-311++G(3df,3pd) calculations also helped in assignment of the experimental bands. A quick consumption of the compound occurred after irradiation of the matrix with UV laser light at λ = 275 nm. Three photofragmentation pathways were proposed, one leading to 2-[1-(1H-diaziren-3- yl)ethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide and molecular nitrogen, a second one giving 2-(1,1-dioxide-3-oxo-1,2-benzisothiazol-2(3H)-yl) propanenitrile and azide, and a third one involving loss of azide from the tetrazole ring and decarbonylation of the saccharyl ring of 1-TE-BZT to give acrylonitrile and 7-thia-8-azabicyclo[4.2.0] octa-1,3,5-triene 7,7 dioxide. The comparison of the relative intensities of the bands of the photoproducts obtained from the three channels allowed us to consider the latter pathway, involving an unprecedented photocleavage of the benzisothiazole (saccharyl) ring, as the preferred photodegradation channel of 1-TE-BZT.
- Ismael, A.,Cristiano, M. L. S.,Borba, A.,Duarte, L.,Giuliano, B. M.,Gomez-Zavaglia, A.
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p. 105 - 116,12
(2020/08/20)
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- Virtual screening and synthesis of new chemical scaffolds as VEGFR-2 kinase inhibitors
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Background: VEGFR-2 tyrosine kinase inhibitors are currently receiving high interest in drug discovery process as anticancer agents. We have used virtual screening techniques in order to discover new scaffolds that can be used for developing new VEGFR-2 k
- Elsayed,El-Araby,Serya,Abouzid
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p. 554 - 560
(2013/02/23)
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- Enantioselective Pd-catalyzed hydrogenation of enesulfonamides
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Asymmetric hydrogenation of cyclic enesulfonamides affords chiral cyclic sulfonamides using Pd(OCOCF3)2/diphosphine complexes as catalysts with up to 98% ee.
- Yu, Chang-Bin,Gao, Kao,Wang, Duo-Sheng,Shi, Lei,Zhou, Yong-Gui
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supporting information; experimental part
p. 5052 - 5054
(2011/06/10)
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- Substituted N-{3-[(1,1-dioxido-1,2-benzothiazol-3-yl)(phenyl)amino]propyl} benzamide analogs as potent Kv1.3 ion channel blockers. Part 2
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We report the synthesis and in vitro activity of a series of novel substituted N-{3-[(1,1-dioxido-1,2-benzothiazol-3-yl)(phenyl)amino]propyl} benzamide analogs. These analogs showed potent inhibitory activity against Kv1.3. Several demonstrated similar po
- Haffner, Curt D.,Thomson, Stephen A.,Guo, Yu,Petrov, Kimberly,Larkin, Andrew,Banker, Pierette,Schaaf, Gregory,Dickerson, Scott,Gobel, Jeff,Gillie, Dan,Condreay, J. Patrick,Poole, Chuck,Carpenter, Tiffany,Ulrich, John
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body text
p. 6989 - 6992
(2011/02/23)
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- N-{3-[(1,1-dioxido-1,2-benzothiazol-3-yl)(phenyl)amino]propyl}benzamide analogs as potent Kv1.3 inhibitors. Part 1
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We report the synthesis and in vitro activity of a series of novel N-{3-[(1,1-dioxido-1,2-benzothiazol-3-yl)(phenyl)amino]propyl}benzamide analogs. These analogs showed potent inhibitory activity against Kv1.3. Several compounds, including compound 8b, sh
- Haffner, Curt D.,Thomson, Stephen A.,Guo, Yu,Schaller, Lee T.,Boggs, Sharon,Dickerson, Scott,Gobel, Jeff,Gillie, Dan,Condreay, J. Patrick
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scheme or table
p. 6983 - 6988
(2010/12/25)
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- Diastereoselective pyrrolidine synthesis via copper promoted intramolecular aminooxygenation of alkenes: Formal synthesis of (+)-monomorine
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The diastereoselectivity of the copper-promoted intramolecular aminooxygenation of various alkene substrates was investigated. a-Substituted 4-pentenyl sulfonamides favor the formation of 2,5-c/s-pyrrolidines (dr > 20:1) giving excellent yields which range from 76-97% while y-substituted substrates favor the 2,3-trans pyrrolidine adducts with moderate selectivity (ca. 3:1). A substrate whose N-substituent was directly tethered to the a-carbon exclusively yielded the 2,5-trans pyrrolidine. The synthetic utility of the method was demonstrated by a short and efficient formal synthesis of (+)-monomorine.
- Paderes, Monissa C.,Chemler, Sherry R.
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supporting information; experimental part
p. 1915 - 1918
(2009/09/25)
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- Method of inhibiting protein tyrosine phosphatase 1B and/or T-cell protein tyrosine phosphatase 4 and/or other PTPases with an Asp residue at position 48
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The present invention provides a method of inhibiting a member of a family of Protein Tyrosine Phosphatases (PTPases, PTPs) such as PTP1B, TC-PTP, CD45, SHP-1, SHP-2, PTPα, PTPε, PTPμ, PTPδ, PTPσ, PTPζ, PTPβ, PTPD1, PTPD2, PTPH1, PTP-MEG1, PTP-LAR, and HePTP by exposing said Ptpase member by administration to a host or otherwise to at least one compound with certain structural, physical and spatial characteristics that allow for the interaction of said compound with specific residues of the active site of PTP1B and/or TC-PTP. These compounds are indicated in the management or treatment of a broad range of diseases such as autoimmune diseases, acute and chronic inflammation, osteoporosis, various forms of cancer and malignant diseases, and type I diabetes and type II diabetes, as well as in the isolation of PTPases and in elucidation or further elucidation of their biological function.
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Page/Page column 131-133
(2010/11/23)
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- INDOLE ACETIC ACIDS EXHIBITING CRTH2 RECEPTOR ANTAGONISM AND USES THEREOF
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The invention relates to indole acetic acid compounds which function as antagonists of the CRTH2 receptor. The invention also relates to the use of these compounds to inhibit the binding of prostaglandin D2 and its metabolites or certain thromboxane metab
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Page/Page column 53
(2008/06/13)
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- Heterocyclic antiviral compounds
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Compounds having the formula I wherein A, m and R1 are herein defined are Hepatitis C virus NS5b polymerase inhibitors. Also disclosed are compositions and methods for inhibiting hepatitis replication, processes for making the compounds and syn
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Page/Page column 18; 35
(2010/11/24)
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- Pseudosaccharin amine derivatives: Synthesis and elastase inhibitory activity
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Pseudosaccharin amines were synthesized from saccharin either by the reaction of pseudosaccharin chloride with amines, or via thiosaccharin which was treated with amines yielding thiosaccharinates, and their reaction with glacial acetic acid. This route gave lower yields than the first way. The synthesis of alkyl [(1,1-dioxo-benzo[d]isothiazol-3-yl)amino]alkanoates as possible Human Leukocyte Elastase (HLE) inhibitors was realized by the reaction between amino acid esters and pseudosaccharin chloride. Hydrolysis of the esters was possible under aqueous basic conditions. Selected compounds were screened for elastase inhibitory activity. Compounds 4k and 4m were found to be reversible inhibitors of HLE with Ki values of 45 μM and 60 μM.
- Rode, Haridas B.,Sprang,Besch,Loose,Otto, Hans-Hartwig
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p. 723 - 731
(2007/10/03)
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- Pyrazolopyrimidines as therapeutic agents
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The present invention is directed to pyrazolopyrimidine derivatives of formula (I) wherein the substituents are defined herein, which are useful as kinase inhibitors and as such are useful for affecting angiogenesis and diseases and conditions associated with angiogenesis.
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- ERYTHROMYCIN A 9-O-PSEUDOSACCHARINYLOXIME DERIVATIVES AND PROCESS FOR THE PREPARATION OF CLARITHROMYCIN USING THE SAME
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The present invention relates to new erythromycin A 9-O-pseudosaccharinyloxime derivatives represented by Formula 1, and to a new method for preparing 6-O-methylerythromycin A (clarithromycin) as macrolide compound, represented by Formula 2, using the same: wherein R1 is hydrogen or a methyl group, and R2 is a trimethylsilyl group.
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- Pyrazolopyrimidines as therapeutic agents
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The present invention provides compounds of Formula I, including pharmaceutically acceptable salts and/or prodrugs thereof, where G, Ra, R2, and R3 are defined as described herein.
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Page/Page column 69
(2010/11/30)
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- Compounds useful as reversible inhibitors of cysteine proteases
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Disclosed are novel cathepsin S, K, F, L and B reversible inhibitory compounds of the formula (Ia) and (Ib) where R2, R3, R4, R5, R6, R7, R8, Het and X are defined herein. The compounds are useful for treating autoimmune and other diseases. Also disclosed are processes for making such novel compounds.
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- Modulators of protein tyrosine phosphateses (PTPases)
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Disclosed are novel compounds, novel compositions, methods of their use, and methods of their manufacture, where such compounds of Formula 1 are pharmacologically useful inhibitors of Protein Tyrosine Phosphatases (PTPase's) including PTP1B, T cell PTP, wherein n, m, X, R1, R2, R3, R4, R5, R6, and R7are defined more fully in the description. The compounds are useful in the treatment of type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, obesity, and other diseases.
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- Novel compounds useful as reversible inhibitors of cysteine proteases
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Disclosed are novel cathepsin S, K, F, L and B reversible inhibitory compounds of the formula (Ia) and (Ib) where R2, R3, R4, R5, R6, R7, R8, Het and X are defined herein. The co
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- Compounds useful as reversible inhibitors of cysteine proteases
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Disclosed are novel cathepsin S, K, F, L and B reversible inhibitory compounds of the formulas (I), (II), (Ia) and (Ib) further defined herein. The compounds are useful for treating autoimmune diseases. Also disclosed are processes for making such novel compounds.
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- Pyrazolopyrimidines as therapeutic agents
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The present invention provides compounds of Formula I, including pharmaceutically acceptable salts and/or prodrugs thereof, where G, R2, and R3 are defined as described herein.
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