- 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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- An efficient one-pot strategy for the synthesis of 4- methylene-2-thiazolidinethiones in water
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A simple and efficient, one-pot strategy for the preparation of 4-methylene-2-thiazolidinethiones has been developed. This protocol involved condensation of primary amines with carbon disulfide in water to generate the dithiocarbamate salts in situ, which coupled with 2,3-dibromopropene, followed by intramolecular cyclization to the corresponding heterocycles in moderate to good yields.
- Hou, Chang-Long,Wei, Mei-Hong,Chen, Li-Li,Liu, Xiao-Ling,Sheng, Shou-Ri
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p. 1561 - 1566
(2020/04/09)
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- Novel 1,3,5-thiadiazine-2-thione derivatives containing a hydrazide moiety: Design, synthesis and bioactive evaluation against phytopathogenic fungi in vitro and in vivo
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A series of novel 1,3,5-thiadiazine-2-thione derivatives bearing a hydrazide moiety were designed, synthesized and evaluated for their antifungal activities against Rhizoctonia solani (Rs), Fusarium graminearum (Fg), Botrytis cinerea (Bc) and Colletotrichum capsici (Cc). The in vitro antifungal bioassays indicated that most of title compounds displayed good selectivity and specificity aganist Rs relative to Fg, Bc and Cc. Strikingly, the title compound N'-(4-chlorophenyl)-2-(5-phenyl-6-thioxo-1,3,5-thiadiazinan-3-yl)acethydrazide (5b) obviously inhibited the Rs growth in vitro with the EC50 value of 0.24 μg/mL, which is approximately 2-folds more effective than the commercialized fungicide carbendazim (0.55 μg/mL). The in vivo anti-Rs effects of title compound 5b were further evaluated on rice leaves with control efficacies of 98.58% at 200 μg/mL and 61.27% at 100 μg/mL. The above researches provide a significant reference for the further structural optimization of 1,3,5-thiadiazine-2-thione derivatives bearing a hydrazide moiety as potential fungicides.
- Wang, Xiaobin,Fu, Xincan,Chen, Min,Wang, An,Yan, Jinghua,Mei, Yudong,Wang, Mengqi,Yang, Chunlong
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supporting information
p. 1419 - 1422
(2019/04/10)
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- Synthesis, in vitro urease inhibitory activity and molecular docking of 3,5-disubstituted thiadiazine-2-thiones
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A series of 3,5-disubstituted-tetrahydro-thiadiazine-2-thione (1-16) have been synthesized, characterized by elemental analysis, infrared (IR), UV-visible, 1H NMR, 13C NMR, and MS spectroscopic techniques, and screened against jack bean urease. Among 16 compounds, compounds (1), (2), (3), (4), (6), (7), and (9) demonstrated excellent urease inhibitory activity with IC50 values (9.8?±?0.5, 11.0?±?0.6, 16.0?±?1.5, 17.2?±?0.5, 15.4?±?0.5, 19.7?±?0.4, and 15.8?±?0.2μM), respectively, even better than the standard thiourea (IC50?=?21?±?0.01μM). However, compound (8) shows an almost same level of inhibition (IC50?=?22.9?±?0.3μM), as like standard. In this work, we reported for the first time urease inhibitory activity of thiadiazine thiones and its molecular docking studies.
- Shah, Muhammad Ishaq Ali,Khan, Rasool,Arfan, Mohammad,Wadood, Abdul,Ghufran, Mehreen
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p. 3073 - 3080
(2019/09/16)
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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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- A versatile approach to hybrid thiadiazine-based molecules by the Ugi four-component reaction
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Aiming at developing a versatile method for the generation of hybrid heterocyclic molecules, we describe a sequential approach comprising the formation of carboxy-functionalized 1,3,5-thiadiazines followed by the Ugi reaction with variation of the amino and the isonitrile components. The method enables the generation of structurally diverse molecular hybrids including peptide, lipid, steroidal and sugar moieties linked to the 1,3,5-thiadiazine scaffold.
- Echemendía, Radell,Fernández, Olivia,Coro, Julieta,Suárez, Margarita,Rivera, Daniel G.
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supporting information
p. 1784 - 1787
(2017/04/13)
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- Enantioselective synthesis of 3,5-disubstituted thiohydantoins and hydantoins
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A mild method to convert optically pure amino acid thiourea and urea derivatives to thiohydantoins and hydantoins, respectively, is described. It provides an efficient way to realize enantioselective synthesis of thiohydantoins and hydantoins with good to high isolated yields and enantiomeric purities. We found that the enantiomeric purities were highly dependent on the reaction conditions including bases, solvents, and temperature.
- Chen, Yu,Su, Li,Yang, Xinying,Pan, Wenyan,Fang, Hao
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p. 9234 - 9239
(2015/11/27)
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- Synthesis of 3-substituted-5-(4-carboxycyclohexylmethyl)-tetrahydro-2h-1,3, 5-thiadiazine-2-thione derivatives as antifibrinolytic and antimicrobial agents
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A series of 3-substituted-5-(4-carboxycyclohexylmethyl)-tetrahydro-2H-1,3, 5-thiadiazine-2-thione derivatives was prepared and examined for antifibrinolytic and antimicrobial activities. Their structures were elucidated by spectral methods. Antifibrinolytic activities of these compounds, were investigated in vitro and compared to tranexamic acid (CAS 1197-18-8). Among the synthesized compounds, 3-methyl-5-(4-carboxycyclohexylmethyl)-tetrahydro-2H-1, 3,5-thiadiazine-2-thione (Ia) was the most prominent one (104 %) when compared to tranexamic acid. Besides, 3-ethyl-5-(4-carboxycyclohexyl-methyl)-tetrahydro- 2H-1,3,5-thiadiazine-2-thione (Ib), 3-isopropyl-5-(4-carboxycyclohexylmethyl)- tetrahydro-2H-1,3,5-thiadiazine-2-thione (Id) and 3-isobutyl-5-(4- carboxycyclohexyl-methyl)-tetrahydro-2H-1,3,5-thiadiazine-2-thione (Ig) showed antifibrinolytic activity similar to tranexamic acid. Antibacterial activities of these compounds against Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis), Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa) and yeast-like fungi (Candida albicans, Candida tropicalis) were investigated by the micro-dilution method and compared with the activity of tranexamic acid, ofloxacin and fluconazole. By this way their minimal inhibitory concentration (MIC), minimal bactericidal concentration (MBC) and minimal fungicidal concentration (MFC) values were determined. Compound Ia exhibited almost equally potent activity against B. subtilis (MIC and MBC: 6.25 μg/mL). Compounds Ib-Id, If-Ig and In exhibited similar bactericidal activity against B. subtilis (MBC: 12.5 μg/mL). Compounds Ik and Im showed bacteriostatic activity against S. aureus. None of the compounds exhibited activity against Gram-negative bacteria. On the other hand, all compounds had potent antifungal activities against the yeast utilized. Among the synthesized compounds, 3-methyl-5-(4-carboxycyclohexylmethyl) -tetrahydro-2H-1,3,5-thiadiazine-2-thione (Ia) seems to be the most effective compound with antifibrinolytic and antimicrobial activity. ECV Editio Cantor Verlag.
- Oezcelik, Azime Berna,Ersan, Seyhan,Ural, Ali Ugur,Oezkan, Semiha,Ertan, Mevluet
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p. 554 - 559
(2008/02/12)
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- Synthesis and antimicrobial activity of new thiazole-2(3H)-thiones containing 1,1,3-trisubstituted cyclobutane
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The reaction of potassium salts of RNHCSSK with 2-chloro-1-(3-methyl-3- phenylcyclobutyl)ethan-1-one in ethanol at 78-80°C afforded new 1,3-thiazole-2(3H)-thiones containing 1,1,3-trisubstituted cyclobutane rings at C-4. The antimicrobial activities of these compounds were also investigated against seven different microorganisms, and some of them were found to be active against several of the microorganisms at higher concentrations.
- Ahmedzade, Misir,Kirilmis, Cumhur,Cukurovali, Alaaddin,Dilsiz, Nihat
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- Synthesis and antimycobacterial activity of 3,5-disubstituted thiadiazine thiones
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A series of 3,5-disubstituted thiadiazine thiones (4-24) have been synthesized by reaction of primary amines with carbon disulphide followed by cyclocondensation of the resulting intermediate with formaldehyde and primary amines or amino acids. The compounds were screened for antitubercular activity in vitro against Mycobacterium tuberculosis H37Rv. Three compounds 4, 12 and 18 showed antimycobacterial activity with MIC 12.5 μg/mL. Compound 4, was tested in vitro against five multidrug resistant (MDR) strains of M. tuberculosis and was found to be active. Compound 4 also exhibited activity in vivo. While all the mice died in the untreated group, the mean survival time (MST) of the compound treated mice was enhanced, 33% mice were surviving in treated group and the load of bacilli in the lung was considerably less in the compound treated group than in the untreated control group.
- Katiyar,Tiwari,Tripathi,Srivastava,Chaturvedi,Srivastava,Srivastava
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p. 4369 - 4375
(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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- Tetrahydro-2H-1,3,5-thiadiazine-5-(4-pyridylcarboxamide)-2-thione derivatives as prodrugs for isoniazid; synthesis, investigations and in vitro antituberculous activity.
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3-Substituted-5-(4-pyridylcarboxamido)tetrahydro-2H-1,3,5-thiad iazine-2- thione derivatives 5a-e were synthesized as prodrugs for isoniazid (INH) to overcome the resistance developed with its therapeutic use. These prodrugs revealed higher lipophilicity compared with INH. Their degradation kinetics were studied in vitro using aqueous buffer solutions of pH values 1.2 and 7.4 was well as biological media of human plasma and rat liver homogenate at 37 degrees C. They were more stable toward enzymatic degradation in biological than in chemical media. Release of INH from these derivatives was detected as a result of both chemical and enzymatic hydrolysis by HPLC. The antimycobacterial activity of the synthesized compounds and INH was tested in vitro against human type of Mycobacterium tuberculosis. They exhibited a greater antitubercular activity than the parent drug. This result is considered as an indicator for an improved permeation of the synthesized prodrugs through mycobacterial cell membranes relative to INH.
- Aboul-Fadl,Hassanin
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p. 244 - 247
(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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- Synthesis and antifungal activities of some new tetrahydro-2H-1,3,5-thiadiazine-2-thiones
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A number of new 3-benzyl-5-[α-(substituted)carboxymethyl]-tetrahydro-2H- 1,3,5-thiadiazine-2-thiones has been synthesized as prodrugs by incorporating the amine group of some amino acid into tetrahydro-2H-1,3,5-thiadiazine-2-thione ring. The compounds have been prepared by the reactions of benzylamine with potassium hydroxide, carbon disulphide formaldehyde and various amino acids. The structures of the compounds have been elucidated by UV, IR, 1H-NMR, mass spectra and elementary analysis. The in vitro activity of these compounds against yeast-like fungi (Candida albicans, C. parapsilosis, C. pseudotropicalis, C. stellatoidea) was investigated by tube dilution method. Their minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) values were determined. All the compounds were found to be active between 3.12- 12.5 μg/ml against the four fungi tested.
- Ertan,Ayyildiz,Yulug
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p. 1182 - 1185
(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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- REACTION OF DITHIOCARBAMIC ACID SALTS WITH 4-SUBSTITUTED 2-THIOLENE- AND 3,4-DISUBSTITUTED THIOLANE 1,1-DIOXIDES. STRUCTURAL STUDIES OF N-PHENYLTHIOLANOTHIAZOLIDINE-2-THIONE 5,5-DIOXIDE
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The reaction of monoalkyl(aryl)dithiocarbamic acid salts with 4-substituted 2-thiolene and 3,4-disubstituted thiolane 1,1-dioxides gave N-alkyl(aryl)thiolanothiazolidine-2-thione 5,5-dioxides, the structure of which was proved by X-ray diffraction studies. 1,1-Dioxothiol-3-en-3-yl esters were obtained with salts of dialkyl(heteryl)dithiocarbamic acids.
- Bezmenova, T. E.,Khaskin, G. I.,Slutskii, V. I.,Dul'nev, P. G.,Zakharov, L. N.,et al.
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p. 668 - 672
(2007/10/02)
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