Several 3‐pyrazolylcarbonyl‐pyrazolo[3,4‐d][1,2,3]triazin‐4‐ones have been prepared from 5‐amino‐1H‐pyrazole‐4‐carbonitriles through a simple sequence. In the first step, diazotization of the corresponding aminopyrazoles afforded pyrazolo[3,4‐d][1,2,3]triazin‐4‐ones. Next, thermal rearrangement of these compounds through nitrogen elimination gave the final products. The proposed mechanism for the ring‐opening of the pyrazolotriazinones to give the pyrazolylcarbonyl‐pyrazolotriazinones involves the generation of an iminoketene intermediate, which reacts with a second molecule of pyrazolotriazinone. The complete mechanism of product formation involving the iminoketene intermediate, and all other reasonable pathways, have been explored in detail through DFT calculations. Furthermore, additional experiments to corroborate the presence of the iminoketene intermediate were carried out.
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.
Heterocyclic compounds structurally related to purine bases have been described as anticonvulsants, antifungal, antiviral, anticancer, enzyme inhibitors, among others. In this work, pyrazolo [3,4-d][1-3]triazin-4-ones (2) and pyrazolo [4,3-d][1-3] triazin-4-ones (3) derivatives were evaluated as xanthine oxidase (XO) inhibitors. Compounds 3 showed the best activity with IC 50 values range of 0.9-2.9 µM. While the inhibition performance of pyrazolotriazinones was not more active than reference inhibitor allopurinol (IC 50 = 0.247 ± 0.004) µM, these nuclei provide a platform for new and more potent XO inhibitors. Accordingly, molecular modeling methods were carried out to understand the compounds-enzyme binding mode. First, we have performed a qualitative SAR study using the MOE™ SAR tool. This study showed three common scaffolds and the most active was identified. These results are certainly valuable and will be taken into account in future synthesis of structurally related compounds. Furthermore, QSAR 2D and 3D studies were performed and structural requirements for the activity are reported. The obtained results led us to present the structural improvements for the rational design and synthesis of new pyrazolotriazinone derivatives with greater xanthine oxidase inhibitory activity than allopurinol.
The Front Cover shows the mechanistic study on the thermal ring‐opening of pyrazolotriazinones to give pyrazolecarbonyl‐pyrazolotriazinones by nitrogen elimination. The proposed mechanism for the thermal reaction of pyrazolotriazinones includes the generation of an iminoketene intermediate, which reacts with a second molecule of pyrazolotriazinone. The comprehensive mechanism of product formation involving the iminoketene intermediate, and all other reasonable pathways, was explored by using DFT calculations. Additional experimental studies to corroborate the presence of an iminoketene intermediate were also carried out. More information can be found in the https://doi.org/10.1002/ejoc.201701538
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