- COMPOUNDS HAVING PDE9A INHIBITORY ACTIVITY, AND PHARMACEUTICAL USES THEREOF
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The present invention provides a compound having a specific chemical structure and having PDE9A inhibitory activity, or a pharmaceutically acceptable salt thereof. The present invention provides a composition containing the compound or a pharmaceutically acceptable salt thereof. The present invention provides a pharmaceutical use, for treating or preventing PDE9A-related diseases, of the compound according to the present invention, a salt thereof, and a composition containing the compound or salt. The present invention also provides a method for treating or preventing PDE9A-related diseases, the method comprising administering an effective amount of the compound according to the present invention, a salt thereof, or a composition containing the compound or salt to a subject in need of treatment.
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Paragraph 0281-0285
(2021/10/15)
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- Synthesis and preliminary anticancer activity assessment of n-glycosides of 2-amino-1,3,4-thiadiazoles
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The addition of 2-amino-1,3,4-thiadiazole derivatives with parallel iodination of differ-ently protected glycals has been achieved using a double molar excess of molecular iodine under mild conditions. The corresponding thiadiazole derivatives of N-glycosides were obtained in good yields and anomeric selectivity. The usage of iodine as a catalyst makes this method easy, inexpen-sive, and successfully useable in reactions with sugars. Thiadiazole derivatives were tested in a panel of three tumor cell lines, MCF-7, HCT116, and HeLa. These compounds initiated biological response in investigated tumor models in a different rate. The MCF-7 is resistant to the tested com-pounds, and the cytometry assay indicated low increase in cell numbers in the sub-G1 phase. The most sensitive are HCT-116 and HeLa cells. The thiadiazole derivatives have a pro-apoptotic effect on HCT-116 cells. In the case of the HeLa cells, an increase in the number of cells in the sub-G1-phase and the induction of apoptosis was observed.
- ?urawska, Katarzyna,Kapica, Patryk,Kasprzycka, Anna,Kudelko, Agnieszka,Olesiejuk, Monika,Papaj, Katarzyna,Skonieczna, Magdalena,Stokowy, Marcin,Szeja, Wies?aw,Walczak, Krzysztof
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- N-(5-phenyl-1, 3, 4-thiadiazole-2-yl) benzamide compound
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The invention belongs to the technical field of medicines, relates to a compound with antitumor activity and a specific chemical structure, and in particular relates to an N-((6, 7-dimethoxyquinoline-4-yl) oxy) methyl)-N-(5-phenyl-1, 3, 4-thiadiazole-2-yl) benzamide compound and a preparation method and an application thereof. The structural general formula of the compound is shown in the specification, wherein an R group is mono-substituted or double-substituted phenyl, fluorophenyl, chlorphenyl, bromophenyl, benzyl, benzyloxy, benzene nitro or trifluoromethyl substituted at 2-position, 3-position or 4-position. Pharmacological studies show that the compound provided by the invention has a relatively remarkable proliferation inhibition effect on HER-2 positive breast cancer cells SK-Br-3, the effect is obviously superior to that of HER-2 negative breast cancer cells MCF-7, the compound can be used for preparing antitumor drugs, and a new way is opened up for deep research and development of tumor drugs in the future. The preparation method provided by the invention is simple and feasible, relatively high in yield and easy for large-scale production.
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Paragraph 0051; 0057; 0066-0068
(2021/06/09)
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- Synthesis, docking, and biological evaluation of thiazolidinone derivatives against hepatitis C virus genotype 4a
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Hepatitis C virus (HCV) genotype 4a (GT4a) is prevalent in Egypt. It did not gain the necessary scientific focus despite its high resistance. Since the crystal structure NS5B (RNA-dependent RNA polymerase) of HCV GT4a has not been resolved until now, homology modeling was conducted to build and validate the 3D model of the enzyme. Ligand binding sites including the allosteric thumb II pocket were detected and used in lead optimization. Sixty new 4-thiazolidinone derivatives have been virtually designed and docked into thumb II site of HCV NS5B GT4a using rigid docking approach. Eighteen compounds (7a–r) that show good docking scores were synthesized and tested in vitro against NS5B GT4a. Compounds 7b and 7n showed the best inhibitory activity (IC50 = 0.338 and 0.342 μM, respectively). Compounds 7a, 7b, 7c, 7d, 7k, 7n, 7q, and 7r that have IC50 values less than 2 μM were assessed for cellular anti-HCV GT4a activity using human hepatoma cell line (Huh 7.5). The percentages of viral growth inhibition are between 79.67 and 94.77%. Compound 7b is the most active in the in vitro and cellular assays and could be considered a potential new lead for future anti-HCV studies. [Figure not available: see fulltext.]
- Al-Behery, Ahmed S.,Elberembally, Kamel M.,Eldawy, Mohammed A.
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p. 1151 - 1165
(2021/04/05)
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- Novel fatty acid-thiadiazole derivatives as potential antimycobacterial agents
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The discovery of antibiotics around the middle twentieth century led to a decrease in the interest in antimycobacterial fatty acids. In order to re-establish the importance of naturally abundant fatty acid, a series of fatty acid-thiadiazole derivatives were designed and synthesized based on molecular hybridization approach. In vitro antimycobacterial potential was established by a screening of synthesized compounds against Mycobacterium tuberculosis H37Rv strain. Among them, compounds 5a, 5d, 5h, and 5j were the most active, with compound 5j exhibiting minimum inhibitory concentration of 2.34?μg/ml against M.tb H37Rv. Additionally, the compounds were docked to determine the probable binding interactions and understand the mechanism of action of most active molecules on enoyl-acyl carrier protein reductases (InhA), which is involved in the mycobacterium fatty acid biosynthetic pathway.
- Mali, Jaishree K.,Sutar, Yogesh B.,Pahelkar, Akshata R.,Verma, Preeti M.,Telvekar, Vikas N.
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p. 174 - 181
(2019/11/03)
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- Antitubercular polyhalogenated phenothiazines and phenoselenazine with reduced binding to CNS receptors
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Targeting energy metabolism in Mycobacterium tuberculosis (Mtb) is a new paradigm in the search for innovative anti-TB drugs. NADH:menaquinone oxidoreductase is a non-proton translocating type II NADH dehydrogenase (NDH-2) that is an essential enzyme in the respiratory chain of Mtb and is not found in mammalian mitochondria. Phenothiazines (PTZs) represent one of the most known class of NDH-2 inhibitors, but their use as anti-TB drugs is currently limited by the wide range of potentially serious off-target effects. In this work, we designed and synthesized a series of new PTZs by decorating the scaffold in an unconventional way, introducing various halogen atoms. By replacing the sulfur atom with selenium, a dibromophenoselenazine 20 was also synthesized. Among the synthesized poly-halogenated PTZs (HPTZs), dibromo and tetrachloro derivatives 9 and 11, along with the phenoselenazine 20, emerged with a better anti-TB profile than the therapeutic thioridazine (TZ). They targeted non-replicating Mtb, were bactericidal, and synergized with rifampin and bedaquiline. Moreover, their anti-TB activity was found to be related to the NDH-2 inhibition. Most important, they showed a markedly reduced affinity to dopaminergic and serotonergic receptors respect to the TZ. From this work emerged, for the first time, as the poly-halogenation of the PTZ core, while permitting to maintain good anti-TB profile could conceivably lead to fewer CNS side-effects risk, making more tangible the use of PTZs for this alternative therapeutic application.
- Barreca, Maria Letizia,Bojarski, Andrzej J.,Cecchetti, Violetta,Cook, Gregory M.,Desantis, Jenny,Felicetti, Tommaso,Franzblau, Scott G.,Handzlik, Jadwiga,Hards, Kiel,Latacz, Gniewomir,Manfroni, Giuseppe,Massari, Serena,Mazzarella, Maria Angela,Nakatani, Yoshio,Nizi, Maria Giulia,Rushton-Green, Rowena,Sabatini, Stefano,Shetye, Gauri,Tabarrini, Oriana,Kolá?, Michal H.,Sata?a, Grzegorz
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- Synthesis and trypanocidal activity of novel pyridinyl-1,3,4-thiadiazole derivatives
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Herein, we present the design, synthesis and trypanocidal evaluation of sixteen new 1,3,4-thiadiazole derivatives from N-aminobenzyl or N-arylhydrazone series. All derivatives were assayed against the trypomastigote form of Trypanosoma cruzi, showing IC50 values ranging from 3 to 226 μM, and a better trypanocidal profile was demonstrated for the 1,3,4-thiadiazole-N-arylhydrazones (3a-g). In this series, the 2-pyridinyl fragment bound to the imine subunit of the hydrazine moiety presented pharmacophoric behavior for trypanocidal activity. Compounds 2a, 11a and 3e presented remarkable activity and excellent selectivity indexes. Compound 2a was also active against the intracellular amastigote form of T. cruzi. Moreover, its corresponding hydrochloride, compound 11a, showed the most promising profile, producing phenotypic changes similar to those caused by posaconazole, a well-known inhibitor of sterol biosynthesis. Thus, 1,3,4-thiadiazole derivative 11a could be considered a good prototype for the development of new drug candidates for Chagas disease therapy.
- Barbosa, Juliana M. C.,Bernardino, Patrícia,Decoté-Ricardo, Débora,Fraga, Carlos A. M.,Freitas, Rosana H. C. N.,Melo, Tatiana G.,Salom?o, Kelly,Sueth-Santiago, Vitor,Wardell, James L.,Wardell, Solange M. S. V.,da Silva, Edson F.
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- Design and development of 1,3,5-triazine-thiadiazole hybrids as potent adenosine A2A receptor (A2AR) antagonist for benefit in Parkinson's disease
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Various studies showed adenosine A2A receptors (A2ARs) antagonists have profound therapeutic efficacy in Parkinsons Disease (PD) by improving dopamine transmission, thus being active in reversing motor deficits and extrapyramidal symptoms related to the disease. Therefore, in the presents study, we have showed the development of novel 1,3,5-triazine-thiadiazole derivative as potent A2ARs antagonist. In the radioligand binding assay, these molecules showed excellent binding affinity with A2AR compared to A1R, with significant selectivity. Results suggest, compound 7e as most potent antagonist of A2AR among the tested series. In docking analysis with A2AR protein model, compound 7e found to be deeply buried into the cavity of receptor lined via making numerous interatomic contacts with His264, Tyr271, His278, Glu169, Ala63, Val84, Ile274, Met270, Phe169. Collectively, our study demonstrated 1,3,5-triazine-thiadiazole hybrid as a highly effective scaffold for the design of new A2A antagonists.
- Agnihotri, Amol Kumar,Bhat, Hans Raj,Giri, Sabeena,Masih, Anup,Pandey, Nidhi,Shrivastava, Jitendra Kumar,Singh, Saumya,Singh, Udaya Pratap
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-
- I2 Promoted Synthesis of 2-Aminothiadiazoles Employing KSCN as a Sulfur Source Under Metal-Free Conditions
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A new three-component strategy from aldehyde, p-toluenesulfonyl hydrazide and potassium thiocyanate for the synthesis of 2-aminothiadiazoles promoted by I2 under metal-free conditions has been described. Potassium thiocyanate was used as an odo
- Zhu, Fuyuan,Yan, Zhaohua,Ai, Chengmei,Wang, Yanmei,Lin, Sen
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supporting information
p. 6561 - 6565
(2019/10/22)
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- Synthesis and evaluation of 1,3,4-oxadiazole derivatives for development as broad-spectrum antibiotics
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The reality and intensity of antibiotic resistance in pathogenic bacteria calls for the rapid development of new antimicrobial drugs. In bacteria, trans-translation is the primary quality control mechanism for rescuing ribosomes arrested during translation. Because trans-translation is absent in eukaryotes but necessary to avoid ribosomal stalling and therefore essential for bacterial survival, it is a promising target either for novel antibiotics or for improving the activities of the protein synthesis inhibitors already in use. Oxadiazole derivatives display strong bactericidal activity against a large number of bacteria, but their effects on trans-translation were recently questioned. In this work, a series of new 1,3,4-oxadiazole derivatives and analogs were synthesized and assessed for their efficiency as antimicrobial agents against a wide range of gram-positive and gram-negative pathogenic strains. Despite the strong antimicrobial activity observed in these molecules, it turns out that they do not target trans-translation in vivo, but they definitely act on other cellular pathways.
- Tresse, Cédric,Radigue, Richard,Gomes Von Borowski, Rafael,Thepaut, Marion,Hanh Le, Hong,Demay, Fanny,Georgeault, Sylvie,Dhalluin, Anne,Trautwetter, Annie,Ermel, Gwennola,Blanco, Carlos,van de Weghe, Pierre,Jean, Micka?l,Giard, Jean-Christophe,Gillet, Reynald
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-
- Novel synthesized SLC-0111 thiazole and thiadiazole analogues: Determination of their carbonic anhydrase inhibitory activity and molecular modeling studies
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In the presented work, we report the design and synthesis of novel SLC-0111 thiazole and thiadiazole analogues (11a–d, 12a–d, 16a–c and 17a–d). A bioisosteric replacement approach was adopted to replace the 4-fluorophenyl tail of SLC-0111 with thiazole and thiadiazole ones, which were thereafter extended with lipophilic un/substituted phenyl moieties. All the newly synthesized SLC-0111 analogues were evaluated in vitro for their inhibitory activity towards a panel of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms (hCA I, II, IX and XII), using a stopped-flow CO2 hydrase assay. All the examined isoforms were inhibited by the primary sulfonamide derivatives (11a–d and 12a–d) in variable degrees with the following KI ranges: 162.6–7136 nM for hCA I, 9.0–833.6 nM for hCA II, 7.9–153.0 nM for hCA IX, and 9.4–94.0 nM for hCA XII. In particular, compounds 12b and 12d displayed 5.5-fold more potent inhibitory activity (KIs = 8.3 and 7.9 nM, respectively) than SLC-0111 (KI = 45 nM) towards hCA IX. Molecular docking study was carried out for 12d within the hCA IX (PDB 3IAI) active site, to justify its inhibitory activity.
- Abo-Ashour, Mahmoud F.,Eldehna, Wagdy M.,Nocentini, Alessio,Ibrahim, Hany S.,Bua, Silvia,Abdel-Aziz, Hatem A.,Abou-Seri, Sahar M.,Supuran, Claudiu T.
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p. 794 - 802
(2019/04/13)
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- Mandelic acid aminoacid aminopeptidase N inhibitor and synthesis method
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The invention relates to a mandelic acid aminoacid aminopeptidase N inhibitor, the general chemical formula of which is in the drawing (The formula is shown in the description.), wherein R1, R2, R3 and R4 are H, F, Cl, Br, NO2, OCH3, CH3 or CH(CH3)3; and R5 is CH3 or CH2CH(CH3)2. Thiosemicarbazide and substituted benzoic acid are utilized to carry out condensation reaction, so that a substituted phenylthiadiazole derivative is produced, the substituted phenylthiadiazole derivative is connected with Boc-protected amino acid by acylation reaction, the protecting group is then removed under the effect of strong acid, and finally, after acylation with trimethylsiloxylphenylacetyl chloride, the target compound is obtained. The route of the synthesis process is short, the raw materials are easyto obtain, and the production cost is low.
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Paragraph 0035; 0036
(2018/07/15)
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- Synthesis and molecular simulation study of furoic peptidomimetic derivatives as potent aminopeptodase N inhibitors
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The aminopeptidase N (APN) plays a critical role in angiogenesis and is over-expressed in tumor cells. In this paper, we report the synthesis and enzyme inhibition assay of furoic peptidomimetic compounds. These new compounds exhibit potent inhibitory ability toward APN with IC50 values lying in the micromolar level. The binding mode of inhibitors in APN active site was explained by a molecular simulation study. These data reveal that ligand coordinating with the catalytic Zn-ion is very important for inhibitory activities.
- Gao, Min,He, Junhua,Xu, Weidong,Lai, Xiaoping,Liu, Fen,Tu, Guogang
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p. 123 - 127
(2018/03/25)
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- Synthesis and evaluation of novel 1,3,4-thiadiazole–fluoroquinolone hybrids as antibacterial, antituberculosis, and anticancer agents
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A series of 5-substituted-1,3,4-thiadiazole-based fluoroquinolone derivatives were designed as potential antibacterial and anticancer agents using a molecular hybridization approach. The target compounds 16–25 were synthesized by reacting the correspondin
- Demirci, Asl?,Karayel, Kaan G?k?e,Tatar, Esra,Okullu, Sinem ?KTEM,Unübol, Nihan,Ta?li, Pakize Neslihan,Kocag?z, Zühtü Tan?l,Sahin, Fikrettin,Kü?ükgüzel, Ilkay
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p. 839 - 858
(2018/06/07)
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- PhI-Catalyzed Intramolecular Oxidative Coupling Toward Synthesis of 2-Amino-1,3,4-Thiadizoles
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A highly efficient method for the synthesis of thiadiazole derivatives via intramolecular oxidative coupling of thiosemicarbazide, using the in situ generated hypervalent iodine(III) reagents is developed. The protocol can be carried out smoothly and provides a variety of thiadiazole derivatives in moderate to excellent yields. Graphical Abstract: A highly efficient method for the synthesis of thiadiazole derivatives via PhI-catalyzed intramolecular oxidative coupling of thiosemicarbazide has been developed.
- Han, Yingzhi,Sun, Yadong,Abdukader, Ablimit,Liu, Bifu,Wang, Duozhi
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p. 3486 - 3491
(2018/09/27)
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- Synthesis and antifungal activities of drimane-amide derivatives from sclareol
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Aim and Objective: Plant diseases are caused by fungal pathogens lead to severe economic losses in many agriculture crops. And the increasing resistance of many fungi to commonly used antifungal agents necessitates the discovery and development of new fungicides. So this study was focused on synthesizing novel skeleton compounds to effectively control plant diseases. Materials and Methods: A series of drimane-amide derivatives were designed, synthesized by aminolysis reaction of amine with intermediate sclareolide which was prepared from sclareol. The structures of all the synthesized compounds were confirmed using1H NMR,13C NMR, and HR-MS (ESI) spectroscopic data. Their in vitro antifungal activity were preliminarily evaluated by using the mycelium growth rate method against five phytopathogenic fungi: Botrytis cinerea, Glomerella cingulata, Alternaria alternate, Alternaria brassicae, and Fusarium graminearum. Results: 23 target compounds were successfully obtained in yields of 52-95%. Compounds358 A2 and A3 displayed favorable inhibitory potency against B. cinerea, G. cingulata and A. brassicae with IC50 values ranging from 3.18 to 10.48 μg/mL. These two compounds displayed higher fungicidal activity than sclareol against all the tested phytopathogenic fungi, and were more effective than the positive control thiabendazole against A. alternate and A. brassicae. The structure-activity relationship studies of compounds A1-10 indicated that both the position and type of substituent on the phenyl ring had significant effects on antifungal activity. Conclusion: The drimane-amide derivatives A2 and A3 were the most promising derivatives and should be selected as new templates for the potential antifungal agents.
- Ma, Miaofeng,Feng, Jili,Wang, Dezhi,Chen, Shu-Wei,Xu, Hui
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p. 501 - 509
(2018/12/13)
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- Metal-free synthesis of 2-aminothiadiazoles via TBHP-Mediated oxidative C-S bond formation
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An efficient one-pot synthesis of 2-amino-1,3,4-thiadiazoles from easily available aldehydes and thiosemicarbazide using TBHP as an oxidant has been described. Notably, these reactions were carried out at room temperature using ethanol as solvent. This is the first example for one-pot synthesis of 2-amino-1,3,4-thiadiazole derivatives from aldehydes. This new synthetic methodology provides a simple procedure utilizing a safer oxidizing system that affords the target products in mild reaction condition with satisfactory yields and wide substrate scope.
- Hatvate, Navnath T.,Ghodse, Shrikant M.,Telvekar, Vikas N.
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supporting information
p. 285 - 290
(2018/02/09)
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- Cyclization–oxidation of Benzylidenehydrazinecarbothioamides by FeCl3.6H2O or ZnCl2.6H2O Catalysts and Synthesis of New 1,3,4-Thiadiazolo-[3,2- α]Pyrimidines
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We report new method for preparation of 2-amino-5-aryl-1,3,4-thiadiazoles by reaction of arylaldehyde with thiosemicarbazide and in the next step via cyclization of 2-aryl hydrazinecarbothioamide in the presence of ZnCl2.6H2O or FeCl3.6H2O. Also, in this research, new substituted 1,3,4-thiadiazolo-[3,2-α]pyrimidines were synthesized by the reaction of 2-amino-5-aryl-1,3,4-thiadiazoles derivatives with DMAD or DEAD in the presence of K2CO3 under reflux conditions. The FT-IR, 1H-NMR, 13C-NMR, elemental analysis and single- crystal X-ray analysis confirm the structures of the products.
- Darehkordi, Ali,Zarezadeh Abarqouei, Behnam,Rahmani, Fariba
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p. 1872 - 1879
(2017/05/29)
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- Thiadiazolodiazepine analogues as a new class of neuromuscular blocking agents: Synthesis, biological evaluation and molecular modeling study
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The synthesis, biological evaluation and molecular modeling study of 6,7-dihydro-[1,3,4] thiadiazolo[3,2-a][1,3]diazepine analogues as new class of neuromuscular blocking agents are described. The new compounds act via competitive mechanism with ACh which
- El-Subbagh, Hussein I.,El-Azab, Adel S.,Hassan, Ghada S.,El-Messery, Shahenda M.,Abdel-Aziz, Alaa A.-M.,El-Taher, Kamal E.H.
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- Synthesis and evaluation of the trypanocidal activity of a series of 1,3,4-thiadiazoles derivatives of R-(+)-limonene benzaldehyde-thiosemicarbazones
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In this study, we synthesized a series of 1,3,4-thiadiazole derivatives of R-(+)-limonene benzaldehyde-thiosemicarbazones (2a–k). We also determined the cytotoxicity in LLCMK2 cells and the activity against epimastigote and trypomastigote forms
- Martins, Solange C.,Desoti, Vania C.,Lazarin-Bidóia, Danielle,Vandresen, Fábio,da Silva, Cleuza C.,Ueda-Nakamura, Tania,Silva, Sueli de O.,Nakamura, Celso V.
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p. 1193 - 1203
(2016/07/06)
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- Design, synthesis, and molecular docking studies of a conjugated thiadiazole-thiourea scaffold as antituberculosis agents
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In view of the emergence and frequency of multidrug-resistant and extensively drug-resistant tuberculosis and consequences of acquired resistance to clinically used drugs, we undertook the design and synthesis of novel prototypes that possess the advantage of the two pharmacophores of thiourea and 1,3,4-thiadiazole in a single molecular backbone. Three compounds from our series were distinguished from the others by their promising activity profiles against Mycobacterium tuberculosis strain H37Rv. Compounds 11 and 19 were the most active representatives with minimum inhibitory concentration (MIC) values of 10.96 and 11.48 μM, respectively. Compound 15 was shown to inhibit M. tuberculosis strain H37Rv with an MIC value of 17.81 μM. Cytotoxicity results in the Vero cell line showed that these three derivatives had selectivity indices between 1.8 and 8.7. In order to rationalize the biological results of our compounds, molecular docking studies with the enoyl acyl carrier protein reductase (InhA) of M. tuberculosis were performed and compounds 11, 15, and 19 were found to have good docking scores in the range of 7.12 to 7.83 kcal/mol.
- Tatar, Esra,Karakus, Sevgi,Kü?ükgüzel, Sükriye Güniz,Okullu, Sinem ?ktem,ünübol, Nihan,Kocag?z, Tanil,De Clercq, Erik,Andrei, Graciela,Snoeck, Robert,Pannecouque, Christophe,Kalayc, Sadik,Sahin, Fikrettin,Sriram, Dharmarajan,Yogeeswari, Perumal,Kü?ükgüzel, Ilkay
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p. 502 - 515
(2016/05/09)
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- Synthesis and biological evaluation of new imidazo[2,1-b][1,3,4]thiadiazole-benzimidazole derivatives
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In this report, we describe the synthesis and biological evaluation of a new series of 2-(imidazo[2,1-b][1,3,4]thiadiazol-5-yl)-1H-benzimidazole derivatives (5a-ac). The molecules were analyzed by 1H NMR, 13C NMR, mass spectral and elemental data. The structure of one of the pre-final compounds, 6-(4-methoxyphenyl)-2-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde (4d) and that of a target compound, 2-[2-methyl-6-(4-methyl phenyl) imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-1H-benzimidazole (5aa) were confirmed by single crystal XRD studies. All the target compounds were screened for in vitro anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv strain. Seven (5c, 5d, 5l, 5p, 5r, 5z and 5aa) out of twenty nine compounds showed potent anti-tubercular activity with a MIC of 3.125 μg/mL. A p-substituted phenyl group (p-tolyl or p-chlorophenyl) in the imidazo[2,1-b][1,3,4]thiadiazole ring and/or a chloro group in the benzimidazole ring enhance anti-tuberculosis activity whereas a nitro group in the benzimidazole ring reduces the activity. In the antibacterial screening, compounds 5i, 5w and 5ac showed promising activity against the tested bacterial strains. Further, antifungal and antioxidant activities of these molecules were also investigated. In the cytotoxicity study, the active antitubercular compounds exhibited very low toxicity against a normal cell line.
- Ramprasad, Jurupula,Nayak, Nagabhushana,Dalimba, Udayakumar,Yogeeswari, Perumal,Sriram, Dharmarajan,Peethambar,Achur, Rajeshwara,Kumar, H. S. Santosh
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- Design of new phenothiazine-thiadiazole hybrids via molecular hybridization approach for the development of potent antitubercular agents
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A new library of phenothiazine and 1,3,4-thiadiazole hybrid derivatives (5a-u) was designed based on the molecular hybridization approach and the molecules were synthesized in excellent yields using a facile single-step chloro-amine coupling reaction between 2-chloro-1-(10H-phenothiazin-10-yl)ethanones and 2-amino-5-subsituted-1,3,4-thiadiazoles. The compounds were evaluated for their in vitro inhibition activity against Mycobacterium tuberculosis H37Rv (MTB). Compounds 5g and 5n were emerged as the most active compounds of the series with MIC of 0.8 μg/mL (~1.9 μM). Also, compounds 5a, 5b, 5c, 5e, 5l and 5m (MIC = 1.6 μg/mL), and compounds 5j, 5k and 5o (MIC = 3.125 μg/mL) showed significant inhibition activity. The structure-activity relationship demonstrated that an alkyl (methyl/npropyl) or substituted (4-methyl/4-Cl/4-F) phenyl groups on the 1,3,4-thiadiazole ring enhance the inhibition activity of the compounds. The cytotoxicity study revealed that none of the active molecules are toxic to a normal Vero cell line thus proving the lack of general cellular toxicity. Further, the active molecules were subjected to molecular docking studies with target enzymes InhA and CYP121.
- Ramprasad, Jurupula,Nayak, Nagabhushana,Dalimba, Udayakumar
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- Photoredox catalysis of intramolecular cyclizations with a reusable silica-bound ruthenium complex
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Photoredox catalysis with the use of a stable, reusable silica-bound chromophore was applied to the intramolecular cyclization of a series of 2-benzylidenehydrazinecarbothioamides to give 5-phenyl-1,3,4-thiadiazol-2-amines. The catalyst was readily prepar
- Barbante, Gregory J.,Ashton, Trent D.,Doeven, Egan H.,Pfeffer, Frederick M.,Wilson, David J. D.,Henderson, Luke C.,Francis, Paul S.
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p. 1655 - 1658
(2015/06/08)
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- A Highly Efficient Diversification of 2-Amino/Amido-1,3,4-oxadiazole and 1,3,4-Thiadiazole Derivatives via Reagent-Based Cyclization of Thiosemicarbazide Intermediate on Solid-Phase
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A 2-amino/amido-1,3,4-oxadiazole and 1,3,4-thiadiazole library has been constructed on solid-phase organic synthesis. The key step on this solid-phase synthesis involves the preparation of polymer-bound 2-amino-1,3,4-oxadiazole and 1,3,4-thiadiazole core
- Yang, Seung-Ju,Choe, Ji-Hye,Abdildinova, Aizhan,Gong, Young-Dae
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p. 732 - 741
(2015/12/23)
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- Improved antiproliferative activity of 1,3,4-thiadiazole-containing histone deacetylase (HDAC) inhibitors by introduction of the heteroaromatic surface recognition motif
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A series of 1,3,4-thiadiazole-containing hydroxamic acids, in accord with the common pharmacophore of histone deacetylase (HDAC) inhibitors (a Zn2+ binding moiety-a linker-a surface recognition motif), was identified as submicromolar HDAC inhibitors by our group. In this study, we continued our efforts to develop 1,3,4-thiadiazole bearing hydroxamate analogues by modifying the surface recognition motif. We found that 1,3,4-thiadiazoles having a heteroaromatic substituent showed better HDAC inhibitory activity in enzymatic assay and higher antiproliferative potency in cellular assay compared to SAHA.
- Guan, Peng,Wang, Lei,Hou, Xuben,Wan, Yichao,Xu, Wenfang,Tang, Weiping,Fang, Hao
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p. 5766 - 5775
(2015/02/02)
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- Synthesis and in vitro evaluation of 1,3,4-thiadiazol-2-yl urea derivatives as novel AChE inhibitors
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1,3,4-Thiadiazole and urea group were hybridized to form new molecular skeleton and 11 compounds were synthesized and evaluated as acetylcholinesterase (AChE) inhibitors. Most of them showed comparable effects in inhibition of AChE, especially compound 6b which exhibited activity with IC50 value 1.17 μM, as strong as galanthamine. This information offered by our research would be valuable for further investigation of structure-activity relationship (SAR) and useful in future research of AChE inhibitors.
- Xue, Xiao-Jian,Wang, Yu-Bin,Lu, Peng,Shang, Hai-Feng,She, Jin-Xiong,Xia, Ling-Xian,Qian, Hai,Huang, Wen-Long
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p. 524 - 527
(2014/07/08)
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- Synthesis, bioevaluation and docking study of 5-substitutedphenyl-1,3,4-thiadiazole-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents
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Since the first histone deacetylase (HDAC) inhibitor (Zolinza, widely known as suberoylanilide hydroxamic acid; SAHA) was approved by the Food and Drug Administration for the treatment of T-cell lymphoma in 2006, the search for newer HDAC inhibitors has attracted a great deal of interest of medicinal chemists worldwide. As a continuity of our ongoing research in this area, we designed and synthesized a series of 5-substitutedphenyl-1,3,4-thiadiazole-based hydroxamic acids as analogues of SAHA and evaluated their biological activities. A number of compounds in this series, for example, N1-hydroxy-N8-(5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl)octandiamide (5b), N1-hydroxy-N8-(5-(3-chlorophenyl-1,3,4-thiadiazol-2-yl)octandiamide (5c) and N1-hydroxy-N8-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)octandiamide (5d), were found to possess potent anticancer cytotoxicity and HDAC inhibition effects. Compounds 5b-d were generally two- to five-fold more potent in terms of cytotoxicity compared to SAHA against five cancer cell lines tested. Docking studies revealed that these hydroxamic acid displayed higher affinities than SAHA toward HDAC8.
- Nam, Nguyen-Hai,Huong, Tran Lan,Dung, Do Thi Mai,Dung, Phan Thi Phuong,Oanh, Dao Thi Kim,Park, Sang Ho,Kim, Kyungrok,Han, Byung Woo,Yun, Jieun,Kang, Jong Soon,Kim, Youngsoo,Han, Sang-Bae
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p. 611 - 618
(2015/02/18)
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- FeCl3-promoted synthesis of 1,3,4-thiadiazoles under combined microwave and ultrasound irradiation in water
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An eco-friendly and efficient synthesis of substituted 1,3,4-thiadiazole derivatives has been developed. This aqueous heterogeneous approach proceeds smoothly and quickly under combined microwave and ultrasound irradiation in the presence of FeCl3.
- Feng, Huangdi,Ying, Xili,Peng, Yanqing,Van Der Eycken, Erik V.,Liu, Chuanduo,Zhao, Shanshan,Song, Gonghua
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p. 681 - 686
(2013/07/26)
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- 2-Heteroarylimino-5-arylidene-4-thiazolidinones as a new class of non-nucleoside inhibitors of HCV NS5B polymerase
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Hepatitis C virus (HCV) NS5B polymerase is an important and attractive target for the development of anti-HCV drugs. Here we report on the design, synthesis and evaluation of twenty-four novel allosteric inhibitors bearing the 4-thiazolidinone scaffold as
- Kü?ükgüzel, Ilkay,Satilmi?, G?khan,Gurukumar,Basu, Amartya,Tatar, Esra,Nichols, Daniel B.,Talele, Tanaji T.,Kaushik-Basu, Neerja
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p. 931 - 941
(2013/11/19)
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- New thiazolidinedione-5-acetic acid amide derivatives: Synthesis, characterization and investigation of antimicrobial and cytotoxic properties
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The present work describes the synthesis, antimicrobial and cytotoxic activity of 2,4-thiazolidinedione- 5-acetic acid amides 3a-n. The structures of the compounds were confirmed by IR, 1H, 13C NMR and elemental analysis. All compounds were tested for antimicrobial activity by twofold serial dilution technique. The preliminary results revealed that the compound 3d exhibits promising antibacterial and antifungal activity. The cytotoxic (MTT) activity of 2,4-thiazolidinedione-5-acetic acid amides were tested in four tumour cell lines. We found that compound 3j inhibited proliferation of HeLa, HT29, A549 and MCF-7 cell lines with IC50 values of 33, 35, 30 and 36 μM, respectively. Springer Science+Business Media, LLC 2011.
- Alegaon, Shankar G.,Alagawadi, Kallanagouda R.
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experimental part
p. 816 - 824
(2012/10/07)
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- Synthesis, biological evaluation, and molecular docking studies of 1,3,4-thiadiazol-2-amide derivatives as novel anticancer agents
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A series of 1,3,4-thiadiazol-2-amide derivatives (5a-5y) have been designed and synthesized, and their biological activities were also evaluated as potential antiproliferation and FAK inhibitors. Among all the compounds, 5h showed the most potent activity
- Yang, Xian-Hui,Xiang, Lu,Li, Xi,Zhao, Ting-Ting,Zhang, Hui,Zhou, Wen-Ping,Wang, Xiao-Ming,Gong, Hai-Bin,Zhu, Hai-Liang
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experimental part
p. 2789 - 2795
(2012/07/27)
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- An efficient synthesis of novel bis-1,3,4-thiadiazolyl-carbamate derivatives based on deoxycholic acid under microwave irradiation
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An easy and efficient method for the synthesis of novel deoxycholic acid bis-1,3,4-thiadiazol-carbamate derivatives under microwave irradiation has been developed. Twelve new methyl 3α,12α-bis-[(5-aryl-1,3,4-thiadiazol-2- yl) carbamoyloxy]-cholan-24-oates
- Zhao, Zhigang,Li, Lin,Liu, Min,Mei, Qinggang
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experimental part
p. 218 - 221
(2012/10/08)
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- Microwave-assisted synthesis of propesticides 1,3,4-thiadiazole aminophosphonates
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A novel and easy synthetic route to diethyl (5-substituted phenyl-1,3,4-thiadiazol-2-ylamino) (substituted phenyl) methylphosphonates has been achieved by the reaction of substituted benzylidene-5-(substituted phenyl)-1,3,4-thiadiazol-2-amines and diethyl phosphite under microwave irradiation. These 1,3,4-thiadiazole aminophosphonates were identified by infrared, 1H NMR, and elemental analyses. The target compounds were obtained in better yields (71-89%) and shorter time (10min) than with conventional heating.
- Wan, Rong,Wang, Peng,Han, Fen,Wang, Yao,Zhang, Jianqiang
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experimental part
p. 864 - 870
(2011/04/22)
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- Microwave-assisted synthesis of 1,3,4-thiadiazole Schiff base derivatives
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A rapid and efficient microwave-assisted synthesis method for the preparation of 1,3,4-thiadiazole Schiff base derivatives is described. These 1,3,4-thiadiazole Schiff bases (5a-h) were identified by IR, 1H NMR, elemental analyses. The target c
- Hu, Jun,Sun, Jianguang,Zhou, Taoyu,Xu, Yanhua
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experimental part
p. 442 - 443
(2011/11/06)
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- 2,5-Disubstituted-1,3,4-oxadiazoles/thiadiazole as surface recognition moiety: Design and synthesis of novel hydroxamic acid based histone deacetylase inhibitors
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The enzymatic inhibition of histone deacetylase activity has come out as a novel and effectual means for the treatment of cancer. Two novel series of 2-[5-(4-substitutedphenyl)-[1,3,4]-oxadiazol/thiadiazol-2-ylamino] -pyrimidine-5-carboxylic acid (tetrahydro-pyran-2-yloxy)-amides were designed and synthesized as novel hydroxamic acid based histone deacetylase inhibitors. The antiproliferative activities of the compounds were investigated in vitro using histone deacetylase inhibitory assay and MTT assay. The synthesized compounds were also tested for antitumor activity against Ehrlich ascites carcinoma cells in Swiss albino mice. The efforts were also made to establish structure-activity relationships among synthesized compounds. The results of the present studying indicates 2,5-disubstituted 1,3,4-oxadiazole/thiadiazole as promising surface recognition moiety for development of newer hydroxamic acid based histone deacetylase inhibitor.
- Rajak, Harish,Agarawal, Avantika,Parmar, Poonam,Thakur, Bhupendra Singh,Veerasamy, Ravichandran,Sharma, Prabodh Chander,Kharya, Murli Dhar
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supporting information; scheme or table
p. 5735 - 5738
(2011/10/09)
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- One pot synthesis of 1,3,4-thiadiazole thiazolidinone derivatives
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One pot synthesis of 2-(substitutedphenyl)-3-[5-(substitutedphenyl)-1,3,4- thiadiazol-2-yl]thiazolidin-4-one was developed by the reaction of 1,3,4-thiadiazole, substituted benzaldehyde and mercaptoacetic acid. These compounds were identified by IR,
- Wang, Peng,Wan, Rong,Han, Fen,Wang, Yao
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experimental part
p. 671 - 673
(2010/03/24)
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- Novel aminopeptidase N inhibitors derived from 1,3,4-thiadiazole scaffold
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The aminopeptidase N (APN/CD13), overexpressed in tumor cells, plays a critical role in angiogenesis. In this study, we report the synthesis and in vitro enzyme inhibition assay of 1,3,4-thiadiazole scaffold compounds. These new compounds have potent inhi
- Tu, GuoGang,Li, ShaoHua,Huang, HuiMing,Li, Gang,Xiong, Fang,Mai, Xi,Zhu, HuaWei,Kuang, BinHai,Xu, Wen Fang
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p. 6663 - 6668
(2008/12/22)
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- Synthesis and anticonvulsant activity of 5-aryl-1,3,4-thiadiazole derivatives
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5-Aryl-1,3,4-thiadiazole derivatives were synthesized and tested for anticonvulsant activity using the pentylenetetrazole-induced lethal convulsion test. The results showed that 2-amino derivatives have anticonvulsant activity (LD50 > 500 mg kg-1) and this effect was not mediated through benzodiazepine receptors. The fluoro electron-withdrawing substituent on the phenyl ring did not potentiate the activity of the compounds.
- Foroumadi,Tabatabai,Gitinezhad,Zarrindast,Shafiee
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