- Diaryl-substituted thiosemicarbazone: A potent scaffold for the development of New Delhi metallo-β-lactamase-1 inhibitors
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The superbug infection caused by New Delhi metallo-β-lactamase (NDM-1) has become an emerging public health threat. Inhibition of NDM-1 has proven challenging due to its shuttling between pathogenic bacteria. A potent scaffold, diaryl-substituted thiosemicarbazone, was constructed and assayed with metallo-β-lactamases (MβLs). The obtained twenty-six molecules specifically inhibited NDM-1 with IC50 0.038–34.7 μM range (except 1e, 2e, and 3d), and 1c is the most potent inhibitor (IC50 = 0.038 μM). The structure-activity relationship of synthetic thiosemicarbazones revealed that the diaryl-substitutes, specifically 2-pyridine and 2-hydroxylbenzene improved inhibitory activities of the inhibitors. The thiosemicarbazones exhibited synergistic antimycobacterial actions against E. coli-NDM-1, resulted a 2–512-fold reduction in MIC of meropenem, while 1c restored 16–256-, 16-, and 2-fold activity of the antibiotic on clinical isolates ECs, K. pneumonia and P. aeruginosa harboring NDM-1, respectively. Also, mice experiments showed that 1c had a synergistic antibacterial ability with meropenem, reduced the bacterial load clinical isolate EC08 in the spleen and liver. This work provided a highly promising scaffold for the development of NDM-1 inhibitors.
- Li, Jia-Qi,Sun, Le-Yun,Jiang, Zhihui,Chen, Cheng,Gao, Han,Chigan, Jia-Zhu,Ding, Huan-Huan,Yang, Ke-Wu
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- Design, synthesis, and biological evaluations of (E)-2-(1-[2-mercapto-4-methyl-1-phenyl-1H-imidazol-5-yl]ethylidene)hydrazinecarbothioamide derivatives as antimicrobial agents
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In recent year, the development of new drugs as antibacterial agents is an important resolution to overcome drug-resistant pathogens. Imidazole derivatives were synthesized using the microwave irradiation method and were characterized using spectral analysis techniques such as proton nuclear magnetic resonance, mass, and Fourier transform infrared spectroscopy. All the analogous were assessed for their in vitro antimicrobial activity and in silico; minimum inhibition concentration values of some conjugates were evaluated against extended spectrum beta-lactamases, vancomycin-resistant enterococci, and Methicillin-resistant Staphylococcus aureus strains from clinical samples. All the analogous were used as ligands in molecular docking and adsorption, distribution, metabolism, and excretion against saDHPS. Furthermore, compounds were also examined for their in vitro antituberculosis and antimalarial activity.
- Daraji, Drashti G.,Jayanthi, Sivaraman,Patel, Hitesh D.,Rajani, Dhanji P.
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supporting information
(2021/12/08)
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- Electrochemical characterization of isatin-thiosemicarbazone derivatives
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Abstract: Herein, we have notably described the electrochemical behavior of four isatin-thiosemicarbazone derivatives. In this regard, cyclic voltammograms of isatin-3-thiosemicarbazone (ITSC), isatin-3-(N4-benzylthiosemicarbazone) (ITSC-Ph), 1-(5-nitro-2-oxoindolin-3-ylidene)thiosemicarbazide (NO2-ITSC) and 1-(5-nitro-2-oxoindolin-3-ylidene)-4-phenylthiosemicarbazide (NO2-ITSC-Ph) have demonstrated an irreversible oxidation process. More specifically, the generation of isatin and thiourea moieties as the final oxidation products was proposed. The cyclic voltammograms also demonstrate irreversible reduction processes of ITSC and ITSC-Ph in three steps. The proposed final products are 3-aminoindolin-2-one and thiourea moieties. In the cyclic voltammograms of NO2-ITSC and NO2-ITSC-Ph, five reduction processes were observed: three of them due to reduction of the nitro group. It was proposed that the formation of 5-hydroxyamino-3-iminoindolin-2-one and the thiourea moieties would be the final products. Graphic abstract: [Figure not available: see fulltext.] Electrochemical characterization of four isatin thiosemicarbazone derivatives is described. The compounds are irreversibly oxidized and reduced. Isatin moieties and thiourea are proposed to be the products generated after oxidation. Considering the reduction processes, the nitro group present at the isatin moiety is also reduced and influences the reduction products generated.
- Bandeira, Katlen Christian Tribuzy,Bohs, Lucas Martins Correa,Bresolin, Leandro,Gervini, Vanessa Carratu,Godoi, Marcelo,Justim, Juliano da Rosa,Martins, Bianca Barreto,Melo, Ana Paula Lopes de,Peixoto, Carlos Roberto de Menezes
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- Insight on a new indolinone derivative as an orally bioavailable lead compound against renal cell carcinoma
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A series of novel 3-indolinone-thiazolidinones and oxazolidinones 4a-k was synthesized via molecular hybridization approach and sequentially evaluated to explore its cytotoxic activity. The cytotoxicity screening pointed toward the N-cyclohexyl thiazolidinone derivative 4f that revealed promising renal cytotoxicity against CAKI-1 and UO-31 renal cancer cell lines with IC50 values 4.74 and 3.99 μM, respectively, which were comparable to those of sunitinib along with good safety threshold against normal renal cells. Further emphasis on compound 4f renal cytotoxicity was achieved via different enzyme assays and CAKI-1 and UO-31 cell cycle analysis. The results were supported by in silico studies to explore its physicochemical, pharmacokinetic and drug-likeness properties. Finally, compound 4f was subjected to an in vivo pharmacokinetic study through two different routes of administration showing excellent oral bioavailability. This research represents compound 4f as a promising candidate against renal cell carcinoma.
- Fouad, Marwa A.,Zaki, Mayssoune Y.,Lotfy, Raghda A.,Mahmoud, Walaa R.
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- Novel indol-3-yl-thiosemicarbazone derivatives: Obtaining, evaluation of in vitro leishmanicidal activity and ultrastructural studies
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Parasitic diseases still represent serious public health problems, since the high and steady emergence of resistant strains is evident. Because parasitic infections are distributed predominantly in developing countries, less toxic, more efficient, safer and more accessible drugs have become desirable in the treatment of the infected population. This is the case of leishmaniasis, an infectious disease caused by a protozoan of the genus Leishmania sp., responsible for triggering pathological processes from the simplest to the most severe forms leading to high rates of morbidity and mortality throughout the world. In the search for new leishmanicidal drugs, the thiosemicarbazones and the indole fragments have been identified as promising structures for leishmanicidal activity. The present study proposes the synthesis and structural characterization of new indole-thiosemicarbazone derivatives (2a-j), in addition to performing in vitro evaluations through cytotoxicity assays using macrophages (J774) activity against forms of Leishmania infantum and Leishmania amazonensis promastigote as well as ultrastructural analyzes in promastigotes of L. infantum. Results show that the indole-thiosemicarbazone derivatives were obtained with yield values varying from 32.09 to 94.64%. In the evaluation of cytotoxicity, the indole-thiosemicarbazone compounds presented CC50 values between 53.23 and 357.97 μM. Concerning the evaluation against L. amazonensis promastigote forms, IC50 values ranged between 12.31 and > 481.52 μM, while the activity against L. infantum promastigotes obtained IC50 values between 4.36 and 23.35 μM. The compounds 2d and 2i tested against L. infantum were the most promising in the series, as they showed the lowest IC50 values: 5.60 and 4.36 respectively. The parasites treated with the compounds 2d and 2i showed several structural alterations, such as shrinkage of the cell body, shortening and loss of the flagellum, intense mitochondrial swelling and vacuolization of the cytoplasm leading the parasite to cellular unviability. Therefore, the indole-thiosemicarbazone compounds are promising because they yield considerable synthesis, have low cytotoxicity to mammalian cells and act as leishmanicidal agents.
- da Silva, Paula Roberta,de Oliveira, Jamerson Ferreira,da Silva, Anekécia Lauro,Queiroz, Camila Marques,Feitosa, Ana Paula Sampaio,Duarte, Denise Maria Figueiredo Araújo,da Silva, Aline Caroline,de Castro, Maria Carolina Accioly Brelaz,Pereira, Valéria Rêgo Alves,da Silva, Rosali Maria Ferreira,Alves, Luiz Carlos,dos Santos, Fábio André Brayner,de Lima, Maria do Carmo Alves
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- A novel 8-nitro quinoline-thiosemicarbazone analogues induces G1/S & G2/M phase cell cycle arrest and apoptosis through ROS mediated mitochondrial pathway
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A series of novel 8-nitro quinoline-based thiosemicarbazone analogues were synthesized and characterized by various spectroscopic and single crystal X-ray analyses. The potent antitumor effects of synthesized compounds towards the cancer cells were evaluated by MTT assay. Amongst, the compound 3a exhibited the highest inhibitory activity and the compounds 3f and 3b were also showed significant activity. The molecular mechanistic studies of cell death have demonstrated that the treated potent compound 3a induced G1/S & G2/M phase cell cycle arrest and induced apoptosis via mitochondrial dysfunction and increased the production of cytotoxic ROS levels. The RT-PCR gene expression analysis revealed that the cell death induced by activation of caspase-3 dependent intrinsic apoptotic signaling pathway. Further, the molecular binding affinity of compounds with estrogen receptor alpha was calculated by molecular docking studies. Thus, novel 8-nitro quinoline-thiosemicarbazone analogues provide a unique tool for breast cancer therapeutic tactics.
- Arasakumar, Thangaraj,Athimoolam, Shunmuganarayanan,Mohan, Palathurai Subramaniam,Saravanan, Arjunan,Shyamsivappan, Selvaraj,Suresh, Thangaraj,Vivek, Raju
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- Synthesis of novel quinoline-thiosemicarbazide hybrids and evaluation of their biological activities, molecular docking, molecular dynamics, pharmacophore model studies, and ADME-Tox properties
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In the present study, a novel series of N-((substituted)carbamothioyl)-2,4-dimethylquinoline-3-carboxamide (7a-7s) was synthesized by microwave-assisted method. Structure of these derivatives was examined by spectroscopic techniques such as 1H NMR, 13C NMR, FT-IR, and ESI-MS. Further, the novel synthesized compounds were evaluated for their in-vitro biological activities against antibacterial, antifungal, antimalarial, and antituberculosis activity as well as for in-silico study. The antimalarial results demonstrated that compounds 7c and 7q (0.02 μg/mL) have notable potency against Plasmodium falciparum compared with chloroquine (0.02 μg/mL); compounds 7l (0.10 μg/mL), 7e, 7s (0.19 μg/mL), 7b, 7p (0.15 μg/mL), 7a, 7f, and 7f (0.25 μg/mL) also exhibited good activity against P. falciparum compared with quinine (0.26 μg/mL) as standard drug. Docking was performed on PFDHFR-TS, given the effect of compounds against the P. falciparum strain was excellent in comparison with standard drug. Molecular docking suggested that compounds 7b, 7i and 7c, 7e, and 7l closely bind with the active site of protein 3JSU and 4DP3, respectively, and compared with biological activity. We have also carried out molecular dynamics simulation on the best dock compound 7e complex with PDB: 3JSU to check the stability of docked complex and their molecular interaction. The calculated ADME-Tox descriptors for the synthesized compounds validated good pharmacokinetics properties, suggesting that these compounds could be used as hit for the development of the new active agents.
- Darji, Drashti G.,Patel, Dhaval B.,Patel, Hitesh D.,Patel, Krupa R.,Rajani, Dhanji P.,Rajani, Smita D.
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- One-pot green synthesis of some novel n-substituted 5-amino-1,3,4-thiadiazole derivatives
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In the current study, a green, one-pot, three-component reaction was performed to prepare novel N-substituted 5-amino-1,3,4-thiadiazole derivatives. The thiadiazoles were obtained from the reaction of a ketene S,S-acetal of Meldrum’s acid or barbituric acid (as key intermediates), hydrazine, and isothiocyanate. The key advantages of this manner include environmentally safe reactions, high yield, appropriate reaction time, simple reaction conditions, and use of a green reaction solvent. The structure of thiadiazoles was determined based on the spectroscopic data.
- Abdul Rahman, Mohd B.,Habibi, Azizollah,Khosravi, Sahar,Shahcheragh, Seyyed M.
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supporting information
p. 517 - 522
(2020/07/17)
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- Design, synthesis and biological evaluation of novel semicarbazone-selenochroman-4-ones hybrids as potent antifungal agents
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A series of novel 2,3-dihydro-4H-1-benzoselenin-4-one (thio)semicarbazone derivatives were designed and synthesized by using molecular hybridization approach. All the target compounds were characterized by HRMS and NMR and evaluated in vitro antifungal activity against five pathogenic strains. In comparison with precursor selenochroman-4-ones, the hybrid molecules in this study showed significant improvement in antifungal activities. Notably, compound B8 showed significant antifungal activity against other strains excluding Aspergillus fumigatus (0.25 μg/mL on Candida albicans, 2 μg/mL on Cryptococcus neoformans, 8 μg/mL on Candida zeylanoides and 2 μg/mL on fluconazole-sensitive strains of Candida albicans). Moreover, compounds B8, B9 and C2 also displayed most potent activities against four fluconazole-resistance strains. Especially the MIC values of the hybrid molecule B8 against fluconazole-resistant strains were in the range of 0.5–2 μg/mL. Therefore, the molecular hybridization approach in this study provided new ideas for the development of antifungal drug.
- Xu, Hang,Su, Xin,Liu, Xiao-qian,Zhang, Kai-peng,Hou, Zhuang,Guo, Chun
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supporting information
(2019/10/19)
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- Inhibitory properties of aromatic thiosemicarbazones on mushroom tyrosinase: Synthesis, kinetic studies, molecular docking and effectiveness in melanogenesis inhibition
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The group of 19 thiosemicarbazones (TSCs) were synthesized and its inhibitory activity toward mushroom tyrosinase and ability to inhibition of melanogenesis in B16 cells were investigated. Moreover, molecular docking of these compounds to the active site of the enzyme was performed. The obtained results allowed to make the structure-activity relationship (SAR) analysis. Kinetic studies revealed that TSCs 1, 2, 11 and 18 have better inhibitory properties than kojic acid, a reference compound, with the best inhibitory constant (Ki) value of 0.38 μM for TSC 2. According to SAR analysis, the smaller and less branched molecules exhibit higher affinity to the enzyme. Melanin production in B16 cells was inhibited by all investigated compounds at micromolar level. Most of compounds studied in this work can be considered as potent inhibitors of tyrosinase and melanogenesis. They may have broad application in food preservatives and cosmetics. Combined results of molecular docking and SAR analysis can be helpful in designing novel tyrosinase inhibitors of desired properties.
- Ha?dys,Goldeman,Jewgiński,Wolińska,Anger,Rossowska,Latajka
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p. 577 - 586
(2018/09/29)
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- An efficient synthesis of novel carbohydrate and thiosemicarbazone hybrid benzimidazole derivatives and their antimicrobial evaluation
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A library of thiosemicarbazide hybrid 2-(aldo-polyhydroxyalkyl)benzimidazole derivatives have been designed and synthesized with simple and eco-friendly methodologies. The structures of the compounds have been elucidated with the aid of elemental analysis, IR, mass and 1H NMR spectral data. These novel synthesized compounds have been evaluated for their antibacterial activity against two gram-positive bacteria (S. aureus and S. pyogenus) and two gram-negative bacteria (P. aeruginosa and E. coli). The title compounds have also been studied for their antifungal activity against C. albicans, A. niger and A. clavatus using the broth dilution technique.
- Panchal, Shyamali N.,Vekariya, Rajesh H.,Patel, Kinjal D.,Prajapati, Shraddha M.,Rajani, Dhanji P.,Rajani, Smita D.,Patel, Hitesh D.
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p. 604 - 612
(2017/01/18)
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- Synthesis, characterization and biological evaluation of novel 1-N-substituted thiocarbomoyl-3-ferrocenyl-2-pyrazoline derivatives
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Some novel 1-N-substituted thiocarbomoyl-3-ferrocenyl-2-pyrazoline derivatives were synthesized and evaluated for in vitro antiamoebic activity against HM1:IMSS strain of Entamoeba histolytica. The results showed that most of the compounds exhibited promising activity (IC50 values in the range of 0.050-1.683 μM) than the reference drug metronidazole (IC50 = 1.78 μM). Active compounds were further screened for cytotoxicity against human embryonic kidney-293 (HEK-293) normal cell lines to ensure their toxic effect and the results revealed that active compounds were least toxic in the concentration range of 2.5-50 μM for 48 h and 2.5-25 μM for 72 h. At 100 μM for 48 h and at 50 μM for 72 h only four compounds 2c, 2h, 2k and 2l showed maximum viability and least cytotoxicity, respectively, concluding that all the screened compounds were least cytotoxic against human embryonic kidney-293 (HEK-293) normal cell lines in the concentration range of 2.5-50 and 2.5-25 μM.
- Parveen, Humaira,Alatawi, Raedah Aiyed Suliman,Khan, Salman Ahmad,Al-Ahmdi, Mohammed Issa,Mukhtar, Sayeed,Azam, Amir,Elsayed, Nadia H.
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p. 1835 - 1840
(2016/07/06)
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- Synthesis, bioactivity, and the anion-binding property of 2-sulfydryl-1,3,4-thiodiazole derivatives
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Two new compounds (1 and 2) containing 2-sulfydryl-1,3,4-thiodiazole have been synthesized and optimized. They both showed wide antibacterial activity for colon bacillus, Staphylococcus aureus, S. albus, dysentery bacillus and inferior activity for Bacillus subtilis. In addition, their binding properties were evaluated for biologically important anions (F-, Cl-, Br-, I-, AcO-, and H2PO4 -) by theoretical investigation, UV-vis, fluorescence, and 1H NMR titration experiments, and they displayed strong binding ability for H2PO4 - without the interference of other anions tested. Especially the binding ability of compound 2 containing anthracene with H2PO4- was 1000 times stronger than that of compound 1 containing nitrobenzene. Two compounds based on 2-sulfydryl-1,3,4-thiodiazole have both properties of anion recognition and antibacterial activity.
- Shang, Xuefang,Li, Wanli,Wei, Xiaofang,Zhang, Huanle,Fu, Zhiyuan,Zhang, Jinlian,Xu, Xiufang
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p. 142 - 149
(2015/03/14)
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- Unexpected formation of 4-alkyl-5-(4-alkylthiosemicarbazido)-4,5-dihydro-1, 2,4-triazine-3(2H)-thiones from 1,3-dialkyl-4,5-bis-(4-alkylthiosemicarbazido) imidazolidin-2-ones in acidic medium
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4-Alkyl-5-(4-alkylthiosemicarbazido)-4,5-dihydro-1,2,4-triazine-3(2H) -thiones are obtained either by heating 1,3-dialkyl-4,5-bis-(4- alkylthiosemicarbazido)imidazolidin-2-ones in acidic medium or the reaction of 1,3-dialkyl-4,5-dihydroxyimidazolidin-2-on
- Gazieva, Galina A.,Poluboyarov, Pavel A.,Kolotyrkina, Natal'ya G.,Lubuzh, Elena D.,Kravchenko, Angelina N.
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- Synthesis of unexpected bifunctionalized thiazoles by nucleophilic attack on allenyl isothiocyanate
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Treatment of allenyl isothiocyanate with a variety of nucleophiles leads to 5-methylthiazoles with a functional group at the 2-position. The same pattern of reactivity is also seen with N-aminophthalimide. In the presence of azide salt, hydrazoic acid, or N,N-disubstituted hydroxylamines, however, allenyl isothiocyanate is converted into bifunctionalized thiazoles. We explain the formation of these products by nucleophilic addition at the isothiocyanato moiety followed by ring closure and an N-N or N-O cleavage reaction to generate short-lived 2-imino-5-methylidenethiazole or 5-methylidenethiazol-2-one. Such intermediates are trapped by addition reactions to give the final heterocyclic compounds. In the case of N,N-disubstituted hydroxylamines, the primary addition products with allenyl isothiocyanate can be detected as unstable intermediates by IR and NMR spectroscopy.
- Jawabrah Al-Hourani, Baker,Richter, Frank,Vrobel, Kai,Banert, Klaus,Korb, Marcus,Rueffer, Tobias,Walfort, Bernhard,Lang, Heinrich
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p. 2899 - 2906
(2014/05/20)
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- Synthesis of some novel thiosemicarbazone derivatives having anti-cancer, anti-HIV as well as anti-bacterial activity
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Some new thiosemicarbazones containing benzimidazole moiety have been synthesized and their ability to inhibit growth of 60 human cancer cell lines, in vitro replication of HIV virus strains as well as inhibition capacity for various bacterial strains have been evaluated. One compound 2-|l-(5-chloro-l//- benzimidazol-2-yl) ethylidene] N-phenylhydrazincarbothioamide (S2) (NSC 92491) has been selected for five dosage screening and shows remarkable anticancer activity along with good anti-HIV and anti-bacterial activities. The structures of all the compounds have been confirmed by FT-IR, NMR, and Mass spectra and by elemental analysis.
- Patel, Hitesh Dahyabhai,Divatia, Saavani Malove,De Clercq, Erik
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p. 535 - 545
(2013/06/26)
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- 3-(1,3,4-Thiadiazole-2-yl)quinoline derivatives: Synthesis, characterization and anti-microbial activity
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A new series of thiadiazoles and intermediate thiosemicarbazones were synthesized from the chloroquinone molecule, with an aim to explore their effect on in vitro growth of microorganisms causing microbial infection. The chemical structures of the compound were elucidated by elemental analysis, FTIR, 1H and 13C NMR and ESI-MS spectral data. In vitro anti-microbial activity was performed against Staphylococcusaureus, Streptococcuspyogenes, Salmonellatyphimurium, and Escherichiacoli. The MIC was detected using the double dilution method. The results were compared by calculating percent inhibit area/μg of the compounds and the standard "amoxicillin". The selected compounds were tested for cytotoxic results using MTT assay H9c2 cardiac myoblasts cell line and the results showed that all the compounds offered remarkable >80% viability to a concentration of 200 μg/mL.
- Bhat, Abdul R.,Tazeem,Azam, Amir,Choi, Inho,Athar, Fareeda
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scheme or table
p. 3158 - 3166
(2011/06/26)
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- Bis-pyrazolines: Synthesis, characterization and antiamoebic activity as inhibitors of growth of Entamoeba histolytica
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The cyclization of chalcone with N-4 substituted thiosemicarbazides under basic condition led to the formation of new compounds, thiocarbamoyl bis-pyrazoline derivatives. The structure of the compounds were elucidated by UV, IR, 1H NMR, 13C NMR and ESI-MS spectral data and thermogravimetric analysis, and their purities were confirmed by elemental analyses. The antiamoebic activity of these complexes was evaluated by microdilution method against HM1:IMSS strain of Entamoeba histolytica and the results were compared with the standard drug, metronidazole. Structure-activity relationship shows that the compound with aromatic substituents at the thiocarbamoyl group was more active than those with the cyclic groups. However, it was clear from the IC50 values that the compounds 15 and 20 are more active and both showed a structural resemblance having an electron withdrawing groups attached to the phenyl ring. MTT assay showed that all the compounds are non-toxic to human kidney epithelial cell line.
- Bhat, Abdul R.,Athar, Fareeda,Azam, Amir
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scheme or table
p. 426 - 431
(2009/04/18)
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- Synthesis and characterization of a new series of hydroxy pyrazolines
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3-Phenyl-1-(thiophen-2-yl)prop-2-en-1-one obtained by Claisen-Schmidt condensation of 2-acetyl thiophene with benzaldehyde was converted into 2,3-dibromo-3-phenyl-1-(thiophen-2-yl)propan-1-one, which on treatment with various thiosemicarbazides in the presence of triethylamine in absolute ethanol, yielded the corresponding hydroxy pyrazolines 3a-h. All the compounds were characterized by IR, 1H NMR, and 13C NMR spectra. Copyright Taylor & Francis Group, LLC.
- Parveen, Humaira,Iqbal, Prince Firdoos,Azam, Amir
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experimental part
p. 3973 - 3983
(2009/04/11)
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- Syntheses of new unsymmetrical and symmetrical diaryl-sulphides and diarylsulphones containing thiazolinyl and thiazolidinonyl moieties using 4,4′-diacetyldiphenylsulphide
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Condensation of 4,4′-diacetyldiphenyl sulphide (2) with variable amounts of thiosemicarbazide (3) in refluxing ethanol and in the presence of catalytic amounts of dry piperidine afforded only 4-acetylthiosemicarbazone- 4′-acetyldiphenyl sulphide (5). Condensation of 2 with excess semicarbazide hydrochloride (4) in the presence of fused sodium acetate and/or piperidine yielded 4,4′-diacetylsemicarbazone diphenyl sulphide (6), whereas use of equimolar amounts of 2 and 4 afforded 4-acetyl-semicarbazone- 4′-acetyldiphenyl sulphide (7). 4-Acetylsemicarbazone-4′- acetylthiosemicarbazone diphenyl sulphide (8) was also obtained via two different routes. The effect of tautomeric structure 5d is discussed. 4-(4″-phenyl-Δ3-thiazoline-2″-acetylazino) -4′-acetyldiphenyl sulphide (9), 4-(5″-carboxyethyl-4″- thiazolidinone-2″-acetylazino)-4′-acetyldiphenyl sulphide (10), 4-(4″-thiazolidinone-2′-acetylazino)-4′-acetyldiphenyl sulphide (11) and 4-(4″-methyl-Δ3-thiazoline-2″- acetylazino)-4′-acetyldiphenyl sulphide (12) were prepared by interaction of 5 with phenacylbromide, bromodiethylmalonate, chloro ethylacetate and chloroacetone, respectively. Sulphides 9-12 were easily condensed with 3 to afford the corresponding 4-(heterocyclic moiety-2″-acetylazino)-4′- acetylthiosemicarbazone diphenyl sulphides 23-26. Oxidation of the prepared sulphides 5-7, 9-12, 23 and 25-26 using H2O2/glacial AcOH mixtures yielded only 4,4′-diacetyldiphenyl sulphone (13) as the main product in every case, besides 3 and 4 in certain cases. Unsymmetrical and symmetrical sulphones 14-22 were obtained starting from 13. The structures of the synthesized compounds are based on IR, 1H-NMR, 13C-NMR and mass spectral data. A theoretical study on some of the prepared compounds using molecular modeling was carried out.
- Abbady,Abdel-Hafez,Kandeel,Abdel-Monem
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p. 622 - 641
(2007/10/03)
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- Thiadiazoles and oxadiazoles and their use as phosphodiesterase-7 inhibitors
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The invention provides 1,3,4-thiadiazoles and 1,3,4-oxadiazoles having the following Formula I: in which, Y is S or O, R1 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, heteroaryl or a polycyclic group, optionally substituted, R2 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl or aryl optionally substituted, R3 is X2—R′3, in which X2 is a binding group and R′3 is cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, heteroaryl, or a polycyclic group; optionally substituted, or their pharmaceutically acceptable derivatives, a compound of Formula I, for their preparation, and processes for pharmaceutical compositions containing methods of using the compounds for the treatment of disorders for which a treatment by a PDE7 inhibitor is relevant.
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- Synthetic peptides, conjugation reagents and methods
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The invention provides methods and compositions useful for making synthetic peptide conjugates. In one embodiment, the invention provides compositions comprising the structure: wherein R is selected from lower substituted or unsubstituted alkyl, O, NH and S and P is an amine protection group. In more particular embodiments, the compositions comprise α-amine protected 4,5-dehydroleucine or α-amine protected (2S)-aminolevulinic acid and/or P is F-moc. These compounds may be incorporated into peptides, for example, peptides comprising a substituted or unsubstituted (2S)-aminolevulinic acid residue, such as (2S)-aminolevulinic acid residue is substituted with an O- or N-linked glycoconjugate, or a detectable label.
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- AZOLYL PIPERAZINYL PHENYL OXAZOLIDINONE ANTIMICROBIALS
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Compounds useful in the preparation of pharmaceutical preparations for the treatment of microbial infection where such compounds are of structural Formula I I or pharmaceutically acceptable salts thereof wherein: R1 is -CHO, -COCH3, -COCHCl2, -COCHF2, -CO2CH3, -SO2CH3, or -COCH2OH; X1 and X2 are independently H, F, or Cl; and Q is a five membered ting heterocycle (azolyl ring) of the general form: wherein A, B, and C are independently oxygen (O), nitrogen (N), sulfur (S) or Carbon (C). In all cases, the piperazine nitrogen atom is attached at the carbon atom of the carbon-nitrogen double bond.
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- Azolyl piperazinyl phenyl oxazolidinone antimicrobials
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Compounds useful in the preparation of pharmaceutical preparations for the treatment of microbial infection where such compounds are of structural Formula I STR1 or pharmaceutically acceptable salts thereof wherein: R1 is --CHO, --COCH3, --COCHCl2, --COCHF2, --CO2 CH3, --SO2 CH3, or --COCH2 OH; X1 and X2 are independently H, F, or Cl; and Q is a five membered ting heterocycle (azolyl ring) of the general form: STR2 wherein A, B, and C are independently oxygen (O), nitrogen (N), sulfur (S) or Carbon (C). In all cases, the piperazine nitrogen atom is attached at the carbon atom of the carbon-nitrogen double bond.
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- 3-aryl-5-alkylthio-4H-1,2,4-triazoles
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This invention relates to novel sulfone and sulfoxide derivatives of 3-aryl-5-alkylthio-4H-1,2,4-triazoles and to the use of 3-aryl-5-alkylthio-, alkylsulfinyl- and alkylsulfonyl-4H-1,2,4-triazoles in the treatment of patients suffering from convulsant seizures.
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- 3-aryl-5-alkylthio-4H-1,2,4-traizoles for treatment of hyperreflexia due to spinal trauma
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This invention relates to the use of 3-aryl-5-alkylthio-4H-1,2,4-triazoles and the corresponding alkylsulfinyl- and alkylsulfonyl-4H-1,2,4-triazoles in the treatment of patients suffering from chronic hyperreflexia due to spinal trauma.
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- 3-aryl-5-alkylthio-4H-1,2,4-triazoles
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This invention relates to derivatives of 3-aryl-5-alkylthio-4H-1,2,4-triazoles, to their pharmacological properties and to their use as muscle relaxants, spasmolytics, anticonvulsants and anxiolytics.
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- SULFOALKYLATION OF ORGANOSULFUR COMPOUNDS
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A new method was developed for the sulfopropylation of 2-mercaptobenzothiazole and 2-mercaptobenzimidazole by direct reaction with 3-hydroxypropanesulfonic acid in hydrochloric or hydrobromic acid or their mixtures at 100-105 deg C for 8-12 h.The reaction of thiourea and thiosemicarbazide with sodium hydroxymethanesulfonate in a weakly alkaline medium gave the disodium salt of N,N'-disulfomethylthiourea and the sodium salt of 1-sulfomethyl-3-thiosemicarbazide respectively.
- Malinauskas, A. A.,Mozolis, V. V.,Gurklene, M. P.
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p. 1377 - 1379
(2007/10/02)
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- Process for the production of 2-amino-5-mercapto-1,3,4-thiadiazole
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2-Amino-5-mercapto-1,3,4-thiadiazoles can be produced in very high yields from thiosemicarbazides and carbon disulfide in aqueous phase by working in the presence of the corresponding ammonium salt of bis-2,5-mercapto-1,3,4-thiadiazole at a temperature above 40° C. Preferably the process is carried out in the presence of the mother liquor from a previous reaction.
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- The Behavior of 6-p-Chlorostyryl-3-thioxo-1,2,4-triazin-5-one toward Phenylmagnesium Bromide
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The action of phenylmagnesium bromide on 6-p-chlorostyryl-3-thioxo-1,2,4-triazin-5-one (1) was studied whereby a mixture of seven products was obtained.These were separated and characterised, and a reasonable mechanism for their formation is presented and discussed.
- Zaher, H.A.,Mohammady, R.,Yehia, A. Ibrahim
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p. 905 - 907
(2007/10/02)
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- 7-Oxabicycloheptane substituted amino prostaglandin analogs and their use in inhibiting platelet aggregation and bronchoconstriction
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7-Oxabicycloheptane substituted amino prostaglandin analogs are provided having the structural formula STR1 and including all stereoisomers thereof. The compounds are cardiovascular agents useful, for example, in the treatment of thrombolytic disease.
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- Thioloesters
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New thioloesters of the formula: STR1 wherein R° represents hydrogen, alkyl, vinyl, cyanomethyl or a protecting radical, R' represents hydrogen or a protecting radical, R represents alkyl, L-2-amino-2-carboxyethyl, phenyl or various heterocyclic radicals, and their syn and anti isomers and mixtures thereof, and metal salts thereof and addition salts thereof with tertiary nitrogen-containing bases, are intermediates useful in the preparation of cephalosporins having anti-bacterial properties.
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- 1,2,4-Triazines
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New thiols of the general formula: STR1 wherein A represents a 2-hydroxy-1-oxoethan-1-yl-2-ylidene or alkoxycarbonylmethyne radical or a nitrogen atom and R represents various substituted alkyl radicals, and their alkali metal and alkaline earth metal salts are useful as intermediates in the preparation of cephalosporins having anti-bacterial properties.
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- 3-Heterocyclic substituted cephem compounds
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Novel cephem compounds having a group of the formula at the 3-position thereof: STR1 wherein X represents oxygen, sulfur or imino, which may be substituted; and B represents hydrogen or a hydroxyl, amino, mercapto or hydrocarbon group, which groups may be substituted, can be prepared by reacting a 3-formylcephem compound with a hydrazine compound of the formula: STR2 wherein the symbols have the same meanings as above, and subjecting the thus obtained compound to an oxidative ring-closure reaction. The objective compounds are found to have a broad antimicrobial spectrum and, in particular, are effective against gram-negative bacteria including Escherichia Coli, Klebsiella pneumoniae, Proteus vulgaris, Proteus mirabilis, Proteus rettgerii, as well as gram positive ones, and have low-toxity. Thus, these compounds may be used for antimicrobial agents in therapeutical purpose.
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- Nonenforced Concerted General-Acid Catalysis of the Dehydration Step in Formaldehyde Thiosemicarbazone Formation
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At pH>6 the formation of formaldehyde thiosemicarbazone proceeds with rate-limiting dehydration of the carbinolamine intermediate, which is at equilibrium with formaldehyde hydrate and thiosemicarbazide (K = 550 M-1).At higher concentrations of formaldehyde a bis(formaldehyde) addition compound is formed, which undergoes dehydration more slowly.The dehydration step is subject to general-acid catalysis by phosphate and phosphonate buffers with α = 0.83.A solvent deuterium isotope effect of kHA/kDA = 2.6 for catalysis by ethylphosphonate monoanion and published evidence support a concerted mechanism of catalysis.The calculated rate constant for formation of the O-protonated carbinolamine is > 104 faster than the observed rate constant for dehydration and the rate constant for expulsion of water from this species is 7 s-1.Thus, it appears that a concerted mechanism can exist when it is not enforced by the nonexistence of the O-protonated species.The secondary α-deuterium isotope effect of KH/kD = 1.06 (1.03 /D) for catalysis by phosphate monoanion suggests an early transition state but other criteria suggest a central or late transition state for C-O cleavage.
- Palmer, John L.,Jencks, William P.
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p. 6466 - 6472
(2007/10/02)
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