- Dithiocarbamates combined with copper for revitalizing meropenem efficacy against NDM-1-producing Carbapenem-resistant Enterobacteriaceae
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The worldwide prevalence of NDM-1-producing Gram-negative pathogens has drastically undermined the clinical efficacy of carbapenems, prompting a need to devise an effective strategy to preserve their clinical value. Here we constructed a focused compound library of dithiocarbamates and systematically evaluated their potential synergistic antibacterial activities combined with copper. SA09-Cu exhibited excellent inhibition against a series of clinical NDM-1-producing carbapenem-resistant Enterobacteriaceae (CRE) in restoring meropenem effect, and slowed down the development of carbapenem resistance. Enzymatic kinetic and isothermal titration calorimetry studies demonstrated that SA09-Cu was a noncompetitive NDM-1 inhibitor. The electron paramagnetic resonance (EPR) and X-ray photoelectron spectroscopy (XPS) revealed a novel inhibition mechanism, which is that SA09-Cu could convert NDM-1 into an inactive state by oxidizing the Zn(II)-thiolate site of the enzyme. Importantly, SA09-Cu showed a unique redox tuning ability, and avoided to be reduced by intracellular thiols of bacteria. In vivo experiments indicated that SA09 combined with CuGlu could effectively potentiate MER's effect against NDM-1-producing E. coli (EC23) in the murine infection model. This study provides a highly promising scaffold in developing novel inhibitors to combat NDM-1-producing CREs.
- Chen, Cheng,Yang, Ke-Wu,Zhai, Le,Ding, Huan-Huan,Chigan, Jia-Zhu
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supporting information
(2021/11/20)
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- Na2S2O8-mediated efficient synthesis of isothiocyanates from primary amines in water
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We have developed two green, practical, and efficient procedures, including a one-pot one, to synthesize isothiocyanates from amines and carbon disulfide via desulfurization with sodium persulfate. Water is used as the solvent. Basic conditions are necessary for good chemoselectivity for isothiocyanates. Structurally diverse linear and branched alkyl amines and aryl amines are readily converted to isothiocyanates by the two procedures in satisfactory yields. Halogens, benzylic C-H bonds, methylthio, nitro, ester, alkenyl, electron-rich or -deficient (hetero)aryls, acetylenyl, and even phenolic and alcoholic hydroxyls are well tolerated. The one-pot procedure in water can also be used to realize the preparation of chiral isothiocyanates from chiral amines, and the modification of bioactive structures with free amino groups. In large-scale preparation, simple and practical purification procedures independent of column chromatography are developed.
- Fu, Zhicheng,Yuan, Wenhao,Chen, Ning,Yang, Zhanhui,Xu, Jiaxi
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supporting information
p. 4484 - 4491
(2018/10/17)
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- Synthesis and antimicrobial activities of 2-thione-3-substituted-5-(4-carboxycyclohexyl-methyl)-tetrahydro-2H-1, 3, 5-thiadiazine derivatives
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(Formula Presented) In this study, 3-substituted-5-(4-carboxycyclohexyl-methyl)-tetrahydro-2H-1, 3, 5-thiadiazine-2-thione which have phenylethyl (1), octyl (2), cyclopropyl (3), 4-methoxybenzyl (4), phenyl (5) groups in position 3 have been synthesized and examined for antimicrobial activities. Their structures were elucidated by spectral method. Antibacterial activities of these compounds against Gram-positive bacteria (Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212), gram-negative bacteria (Escherichia coli ATCC 2592, Pseudomonas aeruginosa ATCC 27853) and yeast-like fungi (Candida albicans ATCC 10231, Candida parapsilosis ATCC 90018) were investigated by the micro-dilution method and compared with the activity of sulbentine, ciprofloxacin and flucanozole. By this way their minimal inhibitory concentration (MIC) values were determinated. Compounds 1-4 exhibited almost equally potent activity against Staphylococcus aureus ATCC 29213 (MIC: 31.2 μg/mL). Compounds 1, 3, 4 showed similar antibacterial activity against Enterococcus faecalis ATCC 29212) (MIC: 62.5 μg/mL). None of the compounds exhibited activity against Gram-negative bacteria. On the other hand, all compounds had potent antifungal activities against the yeast utilized. Compounds 1-4 displayed significant antifungal activity against Candida parapsilosis ATCC 90018 at 7.8 μg/mL concentration while sulbentine was active at 125 μg/mL. Among the synthesized compounds, 3-cyclopropyl-5-(4-carboxycyclohexyl-methyl)-tetrahydro-2H-1, 3, 5-thiadiazine-2-thione(3) seems to be the most effective compound with antibacterial and antifungal activity.
- ?z?elik, Azime Berna,Yilmaz, Günseli,?zkan, Semiha,Ersan, Seyhan
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p. 1059 - 1064
(2016/07/15)
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- Synthesis, spectral, thermal and anti-fungal studies of organotin(IV) thiohydrazone complexes
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The reaction of tribenzyltin(IV) chloride and di(para-chlorobenzyl)tin(IV) dichloride with thiohydrazones derived by condensation of 2-phenylethyl N-thiohydrazide with benzaldehyde, salicaldehyde, p-methylacetophenone and cinnamaldehyde have been investig
- Singh, Rajeev,Kaushik
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experimental part
p. 691 - 696
(2009/05/06)
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- Spectral and thermal studies with anti-fungal aspects of some organotin(IV) complexes with nitrogen and sulphur donor ligands derived from 2-phenylethylamine
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Some complexes of 2-phenylethyl dithiocarbamate, thiohydrazides and thiodiamines with dibenzyltin(IV) chloride, tribenzyltin(IV) chloride and di(para-chlorobenzyl)tin(IV) dichloride have been synthesized and investigated in 1:2 and 1:1 molar ratio. The di
- Singh, Rajeev,Kaushik
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experimental part
p. 669 - 675
(2009/02/07)
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- Organotin(IV) complexes of thiohydrazides and thiodiamines: synthesis, spectral and thermal studies
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Organotin(IV) complexes of tribenzyltin(IV) chloride and di(para-chlorobenzyl)tin(IV) dichloride with thiohydrazides have been reported. The ligands synthesized were bidentate coordinating through sulphur and terminal nitrogen atoms. These form 1:1 metal-
- Singh, Rajeev,Kaushik
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p. 950 - 954
(2007/10/03)
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- New 2H-tetrahydro-1,3,5-thiadiazine-2-thiones incorporating glycine and glycinamide as potential antifungal agents
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The new title derivatives (4 b-h and 5 a-i) were synthesized by reaction of the appropriate primary amine, carbon disulphide, and formaldehyde. These derivatives were prepared in order to study the effects of introducing polar groups at N3 or N5 or at both positions on the biological activity. The compounds were tested for their antifungal activity in vitro against pathogenic (Trichophyton rubrum and Candida albicans), phytopathogenic (Penicillum expansum, Trichoderma hazianum, and Fasarium oxysporum), and aflatoxin-producing (Aspergillus flavus) fungi. These compounds exhibited varied inhibitory effects on growth or sporulation of some tested fungal species.
- Aboul-Fadl, Tarek,Hussein, Mostafa A.,El-Shorbagi, Abdel-Nasser,Khallil, Abdel-Raouf
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p. 438 - 442
(2007/10/03)
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- New carriers for representative peptides and peptide drugs
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3,5-Disubstituted tetrahydro-2H-1,3,5-thiadiazine-2-thione (THTT) derivatives; 4a-g were prepared and found to be a promising prodrug approach for peptide drugs. The pH profile for their degradation in aqueous buffer solutions was determined using HPLC technique and accounted for, in terms of specific base-catalyzed reactions. All of the compounds however, showed high acid-stability. Enzymatic (human serum) hydrolysis of the different derivatives offered an advantageous range of t( 1/4 )'s, the property that permits controlling onset and duration of actions of drugs.
- Aboul-Fadl, Tarek,El-Shorbagi, Abdel-Nasser
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p. 327 - 332
(2007/10/03)
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- Model for delivery of amines through incorporation into a tetrahydro-2H-1,3,5-thiadiazine-2-thione structure
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Phenethylamine 1a (a; n = 2) and benzylamine 1b (b; n = 1) are known in medicinal chemistry as strong vasopressors.Both are excellent substrates for the enzyme monoamine oxidase (MAO).The 2 compounds were incorporated in a highly lipid-soluble and hydrolysis-vulnerable tetrahydrothiadiazine (THTT) target structure in order to modify their pharmacokinetics.Better partition correlations, expressed as log P (calculated and observed) for the synthesized products THTT in comparison to the original compounds 1a,b have been found.One of the THTT derivatives was tested for its liability for chemical hydrolysis and the structure of the hydrolytic product was determined. tetrahydro-2H-1,3,5-thiadiazine-2-thione / phenethylamine / benzylamine / prodrugs / monoamine oxidase inhibitors / partition coefficient / hydrolysis
- El-Shorbagi, A-Na
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- Syntheses and antifungal activities of some 3-(2-phenylethyl)-5-substituted-tetrahydro-2H-1,3,5-thiadiazine-2-thio nes
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Ten new 3-(2-phenethyl)-5-substituted-tetrahydro-2H-1,3, 5-thiadiazine-2-thiones were synthesized by the reaction of phenylethylamine with carbon disulfide and potassium hydroxide, followed by formaldehyde and appropriate amino acids. The structures of th
- Ertan,Bilgin,Palaska,Yulug
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p. 160 - 163
(2007/10/02)
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- Synthesis and antimicrobial activities of some new tetrahydro-2H-1,3,5-thiadiazine-2-thione derivatives of amoxicillin
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A number of 6-[2-(dihydro-5-substituted-6-thioxo-2H-1,3,5-thiadiazine-3(4-H)-yl)- 2-(4-hydroxyphenyl)acetamido]penicillanic acids has been synthesized as prodrugs by incorporating the amine group of amoxicillin trihydrate into tetrahydro-2H-1,3,5-thiadiazine-2-thione ring. The compounds have been prepared by the reaction of various alkyl or aralkyl amines with potassium hydroxide, carbon disulfide, formaldehyde and amoxicillin trihydrate. The structures of the compounds have been elucidated by UV, IR, 1H-NMR spectra and elementary analysis. The in vitro activity of these compounds against gram-positive bacteria (Staphylococcus aureus, Streptococcus faecalis), gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa) and yeast-like fungi (Candida albicans, C. parapsilosis, C. stellatoidea, C. pseudotropicalis) was investigated by the tube dilution method and compared with the activity of amoxicillin trihydrate. By this way their minimal inhibitory concentration (MIC), minimal bactericidal concentration (MBC) and minimal fungicidal concentration (MFC) values were determined. Compound I and Compound VII were significantly more effective than amoxicillin trihydrate against S. aureus (MBC: 6.25 μg/ml). Compound VI and Compound XI were effective against. S. faecalis (MBC: 6.25 μg/ml) and Compound I and Compound VI were effective against E. coli (MBC: 12.5 μg/ml). All of the compounds and amoxicillin trihydrate were ineffective against P. aeruginosa (MIC: >100 μg/ml). Compound IX and Compound X were the most active derivatives against yeast-like fungi; the MFC values for these compounds ranged between 6.25 and 37.5 μg/ml.
- Ertan,Sarac,Yulug
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p. 790 - 795
(2007/10/02)
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