55653-05-9Relevant academic research and scientific papers
Computer-aided molecular design of pyrazolotriazines targeting glycogen synthase kinase 3
Sciú, M. Lourdes,Sebastián-Pérez, Victor,Martinez-Gonzalez, Loreto,Benitez, Rocio,Perez, Daniel I.,Pérez, Concepción,Campillo, Nuria E.,Martinez, Ana,Moyano, E. Laura
, p. 87 - 96 (2018/10/31)
Numerous studies have highlighted the implications of the glycogen synthase kinase 3 (GSK-3) in several processes associated with Alzheimer’s disease (AD). Therefore, GSK-3 has become a crucial therapeutic target for the treatment of this neurodegenerative disorder. Hereby, we report the design and multistep synthesis of ethyl 4-oxo-pyrazolo[4,3-d][1–3]triazine-7-carboxylates and their biological evaluation as GSK-3 inhibitors. Molecular modelling studies allow us to develop this new scaffold optimising the chemical structure. Potential binding mode determination in the enzyme and the analysis of the key features in the catalytic site are also described. Furthermore, the ability of pyrazolotriazinones to cross the blood–brain barrier (BBB) was evaluated by passive diffusion and those who showed great GSK-3 inhibition and permeation to the central nervous system (CNS) showed neuroprotective properties against tau hyperphosphorylation in a cell-based model. These new brain permeable pyrazolotriazinones may be used for key in vivo studies and may be considered as new leads for further optimisation for the treatment of AD.
Synthesis and antimicrobial activity studies of some novel substituted phenylhydrazono-1H-tetrazol-5-ylacetonitriles
Yavuz, Serkan,Aydin, Oezlem,Cete, Servet,Disli, Ali,Yildirir, Yilmaz
scheme or table, p. 120 - 126 (2010/12/20)
In this study, some substituted phenylhydrazono-1H-tetrazol-5-yl- acetonitriles have been synthesized (2a-o, 2a and 2k are known compounds). The synthesized compounds were characterized by spectroscopic methods [Fourier-transform infrared (FTIR), nuclear magnetic resonance (NMR), mass spectroscopy (MS)]. In addition, antimicrobial activities of synthesized compounds were investigated against Bacillus cereus RSKK 863, Escherichia coli ATCC 3521, Pseudomonas aeruginosa ATCC 2921, and Staphylococcus aureus TP32. These compounds had antimicrobial effect against these bacteria (except for 21). Birkhaeuser Boston 2009.
4-Arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects
Kry?tof, Vladimír,Canka?, Petr,Fry?ová, Iveta,Slouka, Jan,Kontopidis, George,D?ubák, Petr,Hajdúch, Marián,Srovnal, Josef,De Azevedo Jr., Walter F.,Orság, Martin,Paprská?ová, Martina,Rol?ík, Jakub,Látr, Ale?,Fischer, Peter M.,Strnad, Miroslav
, p. 6500 - 6509 (2007/10/03)
In a routine screening of our small-molecule compound collection we recently identified 4-arylazo-3,5-diamino-1H-pyrazoles as a novel group of ATP antagonists with moderate potency against CDK2-cyclin E. A preliminary SAR study based on 35 analogues suggests ways in which the pharmacophore could be further optimized, for example, via substitutions in the 4-aryl ring. Enzyme kinetics studies with the lead compound and X-ray crystallography of an inhibitor-CDK2 complex demonstrated that its mode of inhibition is competitive. Functional kinase assays confirmed the selectivity toward CDKs, with a preference for CDK9-cyclin T1. The most potent inhibitor, 4-[(3,5-diamino-1H-pyrazol-4-yl) diazenyl]phenol 31b (CAN508), reduced the frequency of S-phase cells of the cancer cell line HT-29 in antiproliferation assays. Further observed cellular effects included decreased phosphorylation of the retinoblastoma protein and the C-terminal domain of RNA polymerase II, inhibition of mRNA synthesis, and induction of the tumor suppressor protein p53, all of which are consistent with inhibition of CDK9.
