- an interesting isomerization: synthesis of mesoionic 5-arylamino-1,3,4-thiadiazolium-2-thiolates by using ω-bromo-ω-(1H-1,2,4-triazol-1-yl)acetophenone as catalyst
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Mesoionic 5-arylamino-1,3,4-thiadiazolium-2-thiolates 7a-f were prepared by the isomerization of 5-arylamino-1,3,4-thiadiazol-2-thiones 5a-f by using ω-bromo-ω-(1H-1,2,4-triazol-1-yl)acetophenone 6 as catalyst. All the structures of mesoionic synthesized were confirmed by elemental analyses, 1H NMR, IR and MS spectral data. We have also determined the x-ray photoelectron spectroscopy (XPS) of the mesoionic and their precursors. A comparison of XPS spectra between the mesoionic and their precursors showed that the charge separation in mesoionic is distinctly larger than in their precursors.
- Chu, Chang-Hu,Hui, Xin-Ping,Xu, Peng-Fei,Zhang, Zi-Yi,Li, Zhi-Chun,Liao, Ren-An
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- Synthesis of a series of stromelysin-selective thiadiazole urea matrix metalloproteinase inhibitors
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The synthesis and enzyme inhibition data for a series of thiadiazole urea matrix metalloproteinase (MMP) inhibitors are described. A broad screening effort was utilized to identify several thiadiazoles which were weak inhibitors of stromelysin. Optimization of the thiadiazole leads to include an α-amino acid side chain with variable terminal amide substituents provided a series of ureas which were moderately effective stromelysin inhibitors, with K(i)'s between 0.3 and 1.0 μM. The most effective analogues utilized an L-phenylalanine as the amino acid component. In particular, unsubstituted 46 had a K(i) of 710 nM, while the p-fluoro analogue 52 displayed increased potency (100 nM). Stromelysin inhibition was further improved using a pentafluorophenylalanine substituent which resulted in 70, a 14 nM inhibitor. While gelatinase inhibition was generally poor, the use of 1-(2-pyridyl)piperazine as the amide component usually provided for enhanced activity, with 71 inhibiting gelatinase with a K(i) of 770 nM. The combination of this heterocycle with a p-fluorophenylalanine substituent provided the only analogue, 69, with collagenase activity (13 μM). The SAR for analogues described within this series can be rationalized through consideration of the X-ray structure recently attained for 70 complexed to stromelysin. Uniquely, this structure showed the inhibitor to be completely orientated on the left side of the enzyme cleft. These results suggest that thiadiazole urea heterocycles which incorporate a substituted phenylalanine can provide selective inhibitors of stromelysin. Careful selection of the amide substituent can also provide for analogues with modest gelatinase inhibition.
- Jacobsen, E. Jon,Mitchell, Mark A.,Hendges, Susan K.,Belonga, Kenneth L.,Skaletzky, Louis L.,Stelzer, Lindsay S.,Lindberg, Thomas J.,Fritzen, Edward L.,Schostarez, Heinrich J.,O'Sullivan, Theresa J.,Maggiora, Linda L.,Stuchly, Christopher W.,Laborde, Alice L.,Kubicek, Marc F.,Poorman, Roger A.,Beck, Joan M.,Miller, Henry R.,Petzold, Gary L.,Scott, Pam S.,Truesdell, Scott E.,Wallace, Tanya L.,Wilks, John W.,Fisher, Christopher,Goodman, Linda V.,Kaytes, Paul S.,Ledbetter, Stephen R.,Powers, Elaine A.,Vogeli, Gabriel,Mott, John E.,Trepod, Catherine M.,Staples, Douglas J.,Baldwin, Eric T.,Finzel, Barry C.
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- Novel 1,3,4-thiadiazole compounds as potential MAO-A inhibitors-design, synthesis, biological evaluation and molecular modelling
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Monoamine oxidases (MAOs) are important drug targets for the management of neurological disorders. Herein, a series of new 1,3,4-thiadiazole derivatives bearing various alkyl/arylamine moieties as MAO inhibitors were designed and synthesized. All of the compounds were more selective against hMAO-A than hMAO-B. The half maximal inhibitory concentration (IC50) values of most of the compounds were lower than that of the common drug moclobemide (IC50 = 4.664 μM) and compound 6b was proven to be the most active compound (IC50 = 0.060 μM). Moreover, it was seen that compound 6b showed a similar inhibition profile to that of clorgyline (IC50 = 0.048 μM). The inhibition profile was found to be reversible and competitive for compound 6b with MAO-A selectivity. Molecular modelling studies aided in the understanding of the interaction modes between compound 6b and MAO-A. Furthermore, this compound was predicted to have a good pharmacokinetic profile and high BBB penetration. Therefore, such compounds are of interest towards developing new MAO inhibitors.
- Kaplancikli, Zafer Asim,Levent, Serkan,Osmaniye, Derya,?zkay, Yusuf,Acar ?evik, Ulviye,Kaya ?avu?o?lu, Betül,Sa?lik, Begüm Nurpelin
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- Ethenetetracarbonitrile and heterocyclization of symmetrical dithiobiurea as well as thioureidoethylthiourea derivatives
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N,N′-Disubstituted hydrazinecarbothioamides 6a-c and substituted thioureidoethylthioureas 12a-c react with ethenetetracarbonitrile (TCNE) in ethyl acetate or chlorobenzene to form the derivatives of pyrazole 7, 8; thiadiazole 10, 11 thiadiazepine 9, thiadiazepane 13, imidazolidine 14 and diazepine 15.
- Hassan, Alaa A.,Mourad, Aboul-Fetouh E.,El-Shaieb, Kamal M.,Abou-Zied, Ashraf H.
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- Synthesis and characterization of a new series of thiadiazole derivatives as potential anticancer agents
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Cancer is one of the most common causes of death in the world. Despite the importance of combating cancer in healthcare systems and research centers, toxicity in normal tissues and the low efficiency of anticancer drugs are major problems in chemotherapy. Nowadays the aim of many medical research projects is to discover new safer and more effective anticancer agents. 1,3,4-Thiadiazole compounds are important fragments in medicinal chemistry because of their wide range of biological activities, including anticancer activities. The aim of this study was to determine the capacity of newly synthesized 1,3,4-thiadiazole compounds as chemotherapeutic agents. The structures of the obtained compounds were elucidated using 1H-NMR, 13C-NMR and mass spectrometry. Although the thiadiazole derivatives did not prove to be significantly cytotoxic to the tumour tissue cultures, compound 4i showed activity against the C6 rat brain cancer cell line (IC50 0.097 mM) at the tested concentrations.
- ?evik, Ulviye Acar,Osmaniye, Derya,Levent, Serkan,Sa?lik, Begüm Nurpelin,?avu?o?lu, Betül Kaya,?zkay, Yusuf,Kaplancikl, Zafer Aslm
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- Potential inhibitors of human carbonic anhydrase isozymes I and II: Design, synthesis and docking studies of new 1,3,4-thiadiazole derivatives
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In the last years, inhibition of carbonic anhydrase (CA) has emerged as a promising approach for pharmacologic intervention in a variety of disorders such as glaucoma, epilepsy, obesity, and cancer. As a consequence, the design of CA inhibitors (CAIs) is a highly dynamic field of medicinal chemistry. Due to the therapeutic potential of thiadiazoles as CAIs, new 1,3,4-thiadiazole derivatives were synthesized and investigated for their inhibitory effects on hCA I and hCA II. Although the tested compounds did not carry a sulfonamide group, an important pharmacophore for CA inhibitory activity, it was a remarkable finding that most of them were more effective on hCAs than acetazolamide (AAZ), the reference agent. Among these compounds, N′-((5-(4-chlorophenyl)furan-2-yl)methylene)-2-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)thio)acetohydrazide (3) was found to be the most effective compound on hCA I with an IC50 value of 0.14?nM, whereas N′-((5-(2-chlorophenyl)furan-2-yl)methylene)-2-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)thio)acetohydrazide (1) was found to be the most potent compound on hCA II with an IC50 value of 0.15?nM. According to molecular docking studies, all compounds exhibited high affinity and good amino acid interactions similar to AAZ on the both active sites of hCA I and hCA II enzymes.
- Alt?ntop, Mehlika Dilek,Sever, Belgin,?zdemir, Ahmet,Kucukoglu, Kaan,Onem, Hicran,Nadaroglu, Hayrunnisa,Kaplanc?kl?, Zafer As?m
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p. 3547 - 3554
(2017/05/29)
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- Synthesis and in vitro evaluation of thiadiazole derivatives as AChE, Bu-ChE and LOX inhibitors
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N'-Benzylidene-2-[[5-(phenylamino)-1,3,4-thiadiazol-2-yl]thio]acetohydrazide derivatives (5a-p) were synthesized to screen for their AChE, BuChE and LOX inhibitory activity. The CCK-8 assay was also carried out to determine their cytotoxicity against NIH/3T3 cells. The most potent AChE inhibitors were found as compounds 5m (49.79% ± 3.08) and 5p (42.39% ± 3.19), whereas the most potent BuChE inhibitor was found as compound 5d (35.15% ± 2.21). Among these derivatives, N'-(3-methoxybenzylidene)-2-[[5-(phenylamino)-1,3,4-thiadiazol-2-yl]thio]acetohydrazide (5p) can be considered as the most promising AChE inhibitor due to its low cytotoxicity to NIH/3T3 cells (IC50 > 500 μg/mL). N'-(4-Methoxybenzylidene)-2-[[5-(phenylamino)-1,3,4-thiadiazol-2-yl]thio]a-cetohydrazide (5n) exhibited weak inhibition on LOX (%20.65 ± 0.08), whilst the other compounds were not active.
- Altintop, Mehlika Dilek,?zdemir, Ahmet,Abu Mohsen, Usama,Temel, Halide Edip,Akal, Gül?en,Kaplancikli, Zafer Asim
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p. 1062 - 1069
(2015/04/14)
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- Thermolysis of symmetrical dithiobiurea and thioureidoethylthiourea derivatives
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Microwave and thermal heterocyclization of N,N′-disubstituted hydrazinecarbothioamide 1a,b and substituted thioureidoethylthioureas 2a-c as well as 1-phenyl-3[2-(3-phenylthio-ureido)phenyl]-thiourea 6 are reported.
- Hassan, Alaa A.,Mourad, Aboul-Fetouh E.,El-Shaieb, Kamal M.,Abou-Zied, Ashraf H.,Doepp, Dietrich
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p. 535 - 541
(2007/10/03)
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- Synthesis and antifungal activities of ω-(5-arylamino-1,3,4-thiadiazol-2-thio)-ω(1H-1,2,4-triazol-1-yl) acetophenones
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Several ω-(5-arylamino-1,3,4-thiadiazol-2-thiol)-ω-(1H-1,2,4-triazol-1- yl)acetophenones 4a-i have been synthesized. The representative compounds exhibit some antifungal and plant growth regulatory activities. The structures of these compounds have been confirmed by elemental analyses, 1H NMR, IR and MS spectra.
- Chu, Chang-Hu,Hui, Xin-Ping,Xu, Peng-Fei,Zhang, Zi-Yi,Li, Zhi-Chun,Liao, Ren-An
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p. 2436 - 2438
(2007/10/03)
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- Alkali catalyzed thermal cyclization of 1-substituted and 1,6-disubstituted 2,5-dithiobiureas: Formation of 1,2,4-triazolidine-3,5-dithiones and/or 1,3,4-thiadiazoline-5-thiones
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Alkali catalyzed thermal cyclization of 1-alkyl and 1,6-dialkyl-2,5-dithiobiureas (I, R=alkyl, R'=H and R=R'=alkyl) results in the formation of 4-alkyl-1,2,4-triazolidine-3,5-dithiones (V) (alkyl=Me or Et) and 2-alkylamino-Δ2-1,3,4-thiadiazoline-5-thiones (VI) (alkyl=n-Pr or n-Bu).Under the same conditions, 1-alkyl-6-aryl-2,5-dithiobiureas (I, R=alkyl, R'=aryl) give 2-arylamino-Δ2-1,3,4-thiadiazoline-5-thiones (IX) (alkyl=Me, Et, n-Pr or n-Bu) and 4-alkyl-1,2,4-triazolidine-3,5-dithiones (V) also when the alkyl groups are Me or Et.
- Raphael, Elsamma,Joshua, C. P.,Koshy, Lisamma
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p. 635 - 638
(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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