- Synthesis of new 2,5-disubstituted-1,3,4-thiadiazole derivatives and their in vivo anticonvulsant activity
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A series of 2,5-disubstituted-1,3,4-thiadiazole derivatives were synthesized by the reaction of 3-(2-cyanopropan-2-yl)-N-(5-(piperazine-1-yl)-1, 3,4-thiadiazol-2-yl)benzamide with various sulfonyl chlorides and evaluated for their anticonvulsant activity in MES test. Rotorod method was employed to determine the neurotoxicity. The purity of the compounds is confirmed on the basis of their elemental analysis. The structures of all the new compounds are established on the basis of 1H NMR and mass spectral data. Out of fifteen compounds, three were found to be potent anticolvunstants. The same compounds showed no neurotoxicity at the maximum dose administered (100 mg/kg).
- Harish,Mohana,Mallesha
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- Synthesis, solid structure, and optical properties of new thiophene-based alternating π-conjugated copolymers containing 4-alkyl-1,2,4-triazole or 1,3,4-thiadiazole unit as the partner unit
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The synthesis, characterization, and solid-state structure of new thiophene-based alternating π-conjugated polymers containing the 4-alkyl-1,2,4-triazole or 1,2,4-thiadiazole unit as per partner unit were reported. A new thiophene-based CT type alternating copolymers was synthesized to obtain further scope about the packing structure and chemical properties of such CT type alternating π-conjugated copolymers. It was observed that the difference between the syn and anti conformations was small. It was also observed that the calculated density (1.79 g cm-3) according to the packing model agreed with the observed density (1.73 g cm-3).
- Yasuda, Takuma,Imase, Tatsuya,Sasaki, Shintaro,Yamamoto, Takakazu
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- PPAR gamma targeted molecular docking and synthesis of some new amide and urea substituted 1, 3, 4-thiadiazole derivative as antidiabetic compound
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The PPAR-γ agonist enhances the insulin sensitivity and avoids the disorganized hyperglycemic by promoting the insulin guided cellular uptake of blood glucose. Therefore, in the present work PPAR-γ has chosen as the target for the molecular docking study to design an effective agonist of the same. By this research work an effort has been made to prepare amide and urea series of 1, 3, 4-thiadiazole derivatives as 4-substituted-N-(5-(4-(1-piperidino)1-piperidinyl)-1,3,4-(2-thiadiazolyl)benzamide (4a-f) and 1-(4-substitutedphenyl)-3-(5-(4-(1-piperidino)1-piperidinyl)-1,3,4-(2-thiadiazolyl)urea (6a-f). Both the docking score as well as the pharmacological animal study data has been suggested that the electron donating group containing compound 4f and 6f are most potent molecules for the antidiabetic activity close to the standard drug pioglitazone. It was further observed that the unsubstituted aromatic ring containing derivatives have also considerable effect (4a and 6a) than the electron withdrawing containing derivatives. After the comparison of biological data for amide and urea series, it was concluded that the urea (6a-f) series is more effective than the amide series.
- Dewangan, Dhansay,Kashyap, Pranita,Mishra, Achal,Thakur, Alok Singh,Vaishnav, Yogesh,Verma, Santosh Kumar,Verma, Shekhar
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- Quantitative structure–activity relationship of substituted imidazothiadiazoles for their binding against the ecdysone receptor of Sf-9 cells
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Imidazothiadiazoles (ITDs) are a class of potent nonsteroidal ecdysone agonists with larvicidal activity. Previously, we performed the Hansch–Fujita type of quantitative structure–activity relationship (QSAR) analysis for ITD analogs (Yokoi et al., Pestic. Biochem. Physiol. 2015, 120, 40–50). The activity was reasonably explained by hydrophobicity and electronegativity of substituents on the imidazothiadiazole ring system. However, the limited data points (n = 8) hampered the examination of other physicochemical parameters. In the present study, we expanded the library of ITD congeners and evaluated their receptor-binding affinity using intact Sf-9 cells. The QSAR analysis for the expanded set revealed the significance of the third physicochemical parameter, the negative steric effect for long substituents. We also evaluated the larvicidal activity of the synthesized compounds against Spodoptera litura; however, it was not correlated to the binding affinity. The results obtained here suggests that the pharmacokinetic properties must be improved to enhance the larvicidal activity of ITDs.
- Yokoi, Taiyo,Nakagawa, Yoshiaki,Miyagawa, Hisashi
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- Discovery of potent and novel smoothened antagonists via structure-based virtual screening and biological assays
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The Hedgehog (Hh) signaling pathway plays a critical role in controlling patterning, growth and cell migration during embryonic development. Aberrant activation of Hh signaling has been linked to tumorigenesis in various cancers, such as basal cell carcinoma (BCC) and medulloblastoma. As a key member of the Hh pathway, the Smoothened (Smo) receptor, a member of the G protein-coupled receptor (GPCR) family, has emerged as an attractive therapeutic target for the treatment and prevention of human cancers. The recent determination of several crystal structures of Smo in complex with different antagonists offers the possibility to perform structure-based virtual screening for discovering potent Smo antagonists with distinct chemical scaffolds. In this study, based on the two Smo crystal complexes with the best capacity to distinguish the known Smo antagonists from decoys, the molecular docking-based virtual screening was conducted to identify promising Smo antagonists from ChemDiv library. A total of 21 structurally novel and diverse compounds were selected for experimental testing, and six of them exhibited significant inhibitory activity against the Hh pathway activation (IC50 50 lower than 1 μM. The important residues uncovered by binding free energy calculation (MM/GBSA) and binding free energy decomposition were highlighted and discussed. These findings suggest that the novel scaffold afforded by compound 20 can be used as a good starting point for further modification/optimization and the clarified interaction patterns may also guide us to find more potent Smo antagonists.
- Lu, Wenfeng,Zhang, Dihua,Ma, Haikuo,Tian, Sheng,Zheng, Jiyue,Wang, Qin,Luo, Lusong,Zhang, Xiaohu
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- COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF PARASITIC DISEASES
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The present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt thereof; a method for manufacturing the compounds of the invention, solid forms, combinations of pharmacologically active agents, pharmaceutical compositions and methods of using such compounds and solid forms thereof to treat or prevent parasitic diseases, for example malaria.
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Paragraph 0315-0317
(2021/04/23)
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- 1,3,4-thiadiazole heterocyclic compound having hedgehog pathway antagonist activity
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The present invention discloses a 1,3,4-thiadiazole heterocyclic compound having hedgehog pathway antagonist activity, wherein the compound has a structure represented by a general formula I defined in the specification. According to the present invention, the 1,3,4-thiadiazole heterocyclic compound having hedgehog pathway antagonist activity can block tumor cell metastasis regeneration by antagonizing hedgehog pathway so as to achieve significant antitumor effect.
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Paragraph 0042; 0044; 0045-0046
(2019/05/02)
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- PHARMACEUTICAL COMPOSITIONS, METHODS FOR THEIR PREPARATION AND THEIR USE IN THE TREATMENT OF CANCER
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The present application is directed to pharmaceutical compositions comprising derivatives of 6-(4-substitutedphenyl)-2-(substituted piperidine)imidazo[2,1-b][1,3,4]thiadiazol-2-yl], to a method of treating cancer using these compositions and to processes for preparing these derivatives.
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Paragraph 0047-0048
(2018/07/29)
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- NOVEL GPR119 AGONIST COMPOUNDS
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The present invention relates to novel compounds of formula (I), process for preparation of the same and composition comprising these compounds.
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Paragraph 0248-0250
(2017/10/26)
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- A novel Fer/FerT targeting compound selectively evokes metabolic stress and necrotic death in malignant cells
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Disruption of the reprogrammed energy management system of malignant cells is a prioritized goal of targeted cancer therapy. Two regulators of this system are the Fer kinase, and its cancer cell specific variant, FerT, both residing in subcellular compartments including the mitochondrial electron transport chain. Here, we show that a newly developed inhibitor of Fer and FerT, E260, selectively evokes metabolic stress in cancer cells by imposing mitochondrial dysfunction and deformation, and onset of energy-consuming autophagy which decreases the cellular ATP level. Notably, Fer was also found to associate with PARP-1 and E260 disrupted this association thereby leading to PARP-1 activation. The cooperative intervention with these metabolic pathways leads to energy crisis and necrotic death in malignant, but not in normal human cells, and to the suppression of tumors growth in vivo. Thus, E260 is a new anti-cancer agent which imposes metabolic stress and cellular death in cancer cells.
- Elkis, Yoav,Cohen, Moshe,Yaffe, Etai,Satmary-Tusk, Shirly,Feldman, Tal,Hikri, Elad,Nyska, Abraham,Feiglin, Ariel,Ofran, Yanay,Shpungin, Sally,Nir, Uri
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- Synthesis of 2-arylated thiadiazolopyrimidones by Suzuki-Miyaura cross-coupling: a new class of nucleotide pyrophosphatase (NPPs) inhibitors
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Over expression of nucleotide pyrophosphatase (NPPs) activity is associated with chondrocalcinosis, osteoarthritis, type 2 diabetes, neurodegenerative diseases, allergies and cancer metastasis. The potential of NPPs inhibitors as therapeutic agents, and the scarceness of their structure-activity relationship, encouraged us to develop new NPP inhibitors. Specifically, 2-bromo-7-methyl-5-oxo-5H-1,3,4-thiadiazolopyrimidine and its corresponding 6-fluoro derivatives were synthesized via a Suzuki-Miyaura reaction. The cross-coupling reaction with different arylboronic acids gave desired coupling products in good to excellent yields and showed wide functional group tolerance. Furthermore, all compounds were investigated for their potential to inhibit two families of ecto-nucleotidases, i.e. nucleoside triphosphate diphosphohydrolases (NTPDase) and NPPs. Interestingly, our compounds were identified as selective inhibitors of NPPs. Among derivatives 5a-5i, compound 5i (IC50 ± SEM = 0.39 ± 0.01 μM) was found to be the most potent inhibitor of h-NPP1 and compound 5h (IC50 ± SEM = 1.02 ± 0.05 μM) was found to be the most potent inhibitor of h-NPP3. Similarly, for fluorinated thiadiazolopyrimidones, derivative 6e (IC50 ± SEM = 0.31 ± 0.01 μM) exhibited the best inhibition of NPP1 and it was found that this compound exhibited ≈28 fold improvement in inhibitory potential as compared with the reference control i.e. Suramin (IC50 ± SEM = 8.67 ± 1.3 μM). Moreover, homology modelling and molecular docking studies of both inhibitors were carried out to suggest the putative binding mode of inhibitors with the respective enzyme i.e. h-NPP1 and h-NPP3.
- Jafari, Behzad,Yelibayeva, Nazym,Ospanov, Meirambek,Ejaz, Syeda Abida,Afzal, Saira,Khan, Shafi Ullah,Abilov, Zharylkasyn A.,Turmukhanova, Mirgul Z.,Kalugin, Sergey N.,Safarov, Sayfidin,Lecka, Joanna,Sévigny, Jean,Rahman, Qamar,Ehlers, Peter,Iqbal, Jamshed,Langer, Peter
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p. 107556 - 107571
(2016/11/28)
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- SUBSTITUTED PYRIMIDINE COMPOUNDS, COMPOSITIONS AND MEDICINAL APPLICATIONS THEREOF
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The present disclosure relates to pyrimidine compounds of formula (I), their stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, and hydrates thereof. The present disclosure also relates to process of preparation of these pyrimidine compounds, and to pharmaceutical compositions containing them. The compounds of the present disclosure are useful in the treatment, prevention or suppression of diseases and disorders mediated by epidermal growth factor receptor (EGFR) family kinases.
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Paragraph 000110
(2015/03/13)
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- IMIDAZOTHIADIAZOLE DERIVATIVES AS PROTEASE ACTIVATED RECEPTOR 4 (PAR4) INHIBITORS FOR TREATING PLATELET AGGREGATION
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The present invention provides imidazothiadiazole compounds of Formula (I) wherein A, B, D, Rx, R1, R2, R3, X1, X2 and s are as defined herein, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate form thereof, wherein all of the variables are as defined herein. These compounds are inhibitors of platelet aggregation and thus can be used as medicaments.
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Paragraph 00179; 00180
(2013/11/18)
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- Discovery of a potent thiadiazole class of histamine H3 receptor antagonist for the treatment of diabetes
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A series of novel 2-piperidinopiperidine thiadiazoles were synthesized and evaluated as new leads of histamine H3 receptor antagonists. The 4-(5-([1,4-bipiperidin]-1-yl)-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)morpholine (5u) displayed excellent potency and ex vivo receptor occupancy. Compound 5u was also evaluated in vivo for antidiabetic efficacy in STZ diet-induced obesity type 2 diabetic mice for 2 or 12 days. Non-fasting glucose levels were significantly reduced as compared with vehicle-treated mice. In addition, 5u dose dependently blocked the increase of HbA1c after 12 days of treatment.
- Rao, Ashwin U.,Shao, Ning,Aslanian, Robert G.,Chan, Tin-Yau,Degrado, Sylvia J.,Wang, Li,McKittrick, Brian,Senior, Mary,West, Robert E.,Williams, Shirley M.,Wu, Ren-Long,Hwa, Joyce,Patel, Bhuneshwari,Zheng, Shuqin,Sondey, Christopher,Palani, Anandan
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supporting information; experimental part
p. 198 - 202
(2012/04/23)
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- Discovery of potent and liver-targeted stearoyl-CoA desaturase (SCD) inhibitors in a bispyrrolidine series
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Inhibition of stearoyl-CoA desaturase (SCD) activity represents a potential novel mechanism for the treatment of metabolic disorders including obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed SCD inhibitors, our research efforts have been focused on the search for new and structurally diverse liver-targeted SCD inhibitors. This work has led to the discovery of novel, potent and structurally diverse liver-targeted bispyrrolidine SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model.
- Lachance, Nicolas,Gareau, Yves,Guiral, Sebastien,Huang, Zheng,Isabel, Elise,Leclerc, Jean-Philippe,Leger, Serge,Martins, Evelyn,Nadeau, Christian,Oballa, Renata M.,Ouellet, Stephane G.,Powell, David A.,Ramtohul, Yeeman K.,Tranmer, Geoffrey K.,Trinh, Thao,Wang, Hao,Zhang, Lei
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scheme or table
p. 980 - 984
(2012/03/26)
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- TRISUBSTITUTED BORON-CONTAINING MOLECULES
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This invention largely relates to 3,4,6-trisubstituted benzoxaborole compounds, and their use for treating bacterial infections.
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Page/Page column 276
(2011/02/24)
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- HETEROCYCLIC DERIVATIVES AS INHIBITORS OF STEAROYL-COENZYME A DELTA-9 DESATURASE
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Heterocyclic compounds of structural formula (I), or a pharmaceutically acceptable salt thereof, wherein W is a R1— substituted heteroaryl, R1 is an heteroaryl ring substituted with an ester or carboxylic acid containing radical, X-T is N—CR5R6, C═CR5 or CR13—CR5R6, Y is a bond or —C(O)—, a and b represent an integer selected from 1 to 4, and Ar is an optionally substituted phenyl or naphtyl, are inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD) The heterocyclic compounds are useful for the prevention and treatment of conditions related to abnormal lipid synthesis and metabolism, including cardiovascular disease, atherosclerosis, obesity, diabetes, neurological disease, Metabolic Syndrome, insulin resistance, cancer, liver steatosis, and non-alcoholic steatohepatitis.
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Page/Page column 49-50
(2011/12/14)
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- 6-PHENYL-2-[((PIPERIDIN-4-YLMETHYL)-PIPERAZIN-1YL) OR PIPERAZIN 1-YLMETHYL)-PIPERIDIN-1-YL)]-IMIDAZO[2,1-B][1,3,4]THIADIAZOLE DERIVATIVES AND THEIR USE
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The present invention is directed to novel heterocyclic compounds, their synthesis and pharmaceutical compositions comprising them for the treatment of disorders, in particular, cancer.
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Page/Page column 17
(2010/09/17)
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- IMIDAZOTHIADIAZOLES DERIVATIVES
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Novel imidazo[2,1-b][1,3,4]thiadiazole derivatives of formula (I) wherein R1 and R2 have the meaning according to claim 1, are inhibitors of TGF-beta receptor I kinase, and can be employed, inter alia, for the treatment of tumors.
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Page/Page column 53
(2010/04/03)
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- HETEROCYCLIC DERIVATIVES AS INHIBITORS OF STEAROYL-COENZYME A DELTA-9 DESATURASE
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Heterocyclic compounds of structural formula (I), or a pharmaceutically acceptable salt thereof, wherein W is a R1-substituted heteroaryl, R1 is an heteroaryl ring substituted with an ester or carboxylic acid containing radical, X-T is N-CR5R6, C=CR5 or CR13-CR5R6, Y is a bond or -C(O)-, a and b represent an integer selected from 1 to 4, and Ar is an optionally substituted phenyl or naphtyl, are inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD) The heterocyclic compounds are useful for the prevention and treatment of conditions related to abnormal lipid synthesis and metabolism, including cardiovascular disease, atherosclerosis, obesity, diabetes, neurological disease, Metabolic Syndrome, insulin resistance, cancer, liver steatosis, and non-alcoholic steatohepatitis.
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Page/Page column 80
(2010/09/17)
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- HETEROCYCLIC COMPOUNDS AS INHIBITORS OF STEAROYL-COENZYME A DELTA-9 DESATURASE
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Heterocyclic compounds of structural formula I are inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD). The compounds of the present invention are useful for the prevention and treatment of conditions related to abnormal lipid synthesis and metabolism, including cardiovascular disease; atherosclerosis; obesity; diabetes; neurological disease; Metabolic Syndrome; insulin resistance; cancer, liver steatosis; and non-alcoholic steatohepatitis.
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Page/Page column 58
(2010/11/03)
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- IMIDAZOLOTHIADIAZOLES FOR USE AS PROTEIN KINASE INHIBITORS
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There is provided compounds of formula (I), wherein Z, M, R1, X, R2, R3 and B have meanings given in the description, and pharmaceutically-acceptable esters, amides, solvates or salts thereof, which compounds are useful in the treatment of diseases in which inhibition of a protein kinase (e.g. a PIM family kinase or PI3-K) is desired and/or required, and particularly in the treatment of cancer.
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Page/Page column 50-51
(2009/05/29)
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- Heterocyclic Derivatives for the Treatment of Diseases Mediated by Stearoyl-Coa Desaturase Enzymes
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Methods of treating an SCD-mediated disease or condition in a mammal, preferably a human, are disclosed, wherein the methods comprise administering to a mammal in need thereof a compound of formula (I): where x, y, G, J, K, L, M, W, V, R2, R3, R5, R5a, R6, R6a, R7, R7a, R8 and R8a are defined herein. Pharmaceutical compositions comprising the compounds of formula (I) are also disclosed.
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Page/Page column 18
(2008/12/04)
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- AZACYCLOPENTANE DERIVATIVES AS INHIBITORS OF STEAROYL-COENZYME A DELTA-9 DESATURASE
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Azacyclopentane derivatives of structural formula (I) are selective inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD1) relative to other known stearoyl-coenzyme A desaturases. The compounds of the present invention are useful for the prevention and treatment of conditions related to abnormal lipid synthesis and metabolism, including cardiovascular disease; atherosclerosis; obesity; diabetes; neurological disease; metabolic syndrome; insulin resistance; liver steatosis; and non-alcoholic steatohepatitis.
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Page/Page column 46-47
(2008/06/13)
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- 1,3,4-THIADIAZOLES USEFUL FOR THE TREATMENT OF CMV INFECTIONS
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The present invention presents novel 1,3,4-thiadiazole derivatives of formula I which have useful antiviral activity against herpes virus, cytomegalovirus (CMV).
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- 8-hydroxy-7-substituted quinolines as anti-viral agents
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The present invention provides for 8-hydroxy-7-substituted quinoline compounds such as formula III These compounds are useful as anti-viral agents. Specifically, these compounds have anti-viral activity against the herpes virus, cytomegalovirus (CMV). Many of these compounds are also active against other herpes viruses, such as the varicella zoster virus, the Epstein-Barr virus, the herpes simplex virus and the human herpes virus type 8 (HHV-8).
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- 1,3,4-thiadiazoles useful for the treatment of CMV infections
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The present invention presents novel 1,3,4-thiadiazole derivatives of formula I which have useful antiviral activity against herpes virus, cytomegalovirus (CMV).
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- ANOMALOUS REARRANGEMENT OF 1,2,3-THIADIAZOLES TO 1,2,3-TRIAZOLES
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The rearrangement of 5-amino-1,2,3-thiadiazoles under the influence of halogen-containing oxidizing to bis(triazolyl) disulfides was observed.Ammonia reduces the disulfides obtained to 5-mercapto-1,2,3-triazoles.
- Shafran, Yu. M.,Bakulev, V. A.,Shevyrin, V. A.,Kolobov, M. Yu.
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p. 724 - 729
(2007/10/02)
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- Method of controlling aquatic weeds
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A method of controlling aquatic weeds which comprises adding to a body of water containing the aquatic weeds a substituted 1-thiadiazolyl-3-arylurea in sufficient quantity to kill the weeds.
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