5399-44-0Relevant articles and documents
Revisiting Pyrazolo[3,4- d]pyrimidine Nucleosides as Anti- Trypanosoma cruzi and Antileishmanial Agents
Bouton, Jakob,Ferreira De Almeida Fiuza, Ludmila,Cardoso Santos, Camila,Mazzarella, Maria Angela,De Nazaré Correia Soeiro, Maria,Maes, Louis,Karalic, Izet,Caljon, Guy,Van Calenbergh, Serge
, p. 4206 - 4238 (2021/05/04)
Chagas disease and visceral leishmaniasis are two neglected tropical diseases responsible for numerous deaths around the world. For both, current treatments are largely inadequate, resulting in a continued need for new drug discovery. As both kinetoplastid parasites are incapable of de novo purine synthesis, they depend on purine salvage pathways that allow them to acquire and process purines from the host to meet their demands. Purine nucleoside analogues therefore constitute a logical source of potential antiparasitic agents. Earlier optimization efforts of the natural product tubercidin (7-deazaadenosine) involving modifications to the nucleobase 7-position and the ribofuranose 3′-position led to analogues with potent anti-Trypanosoma brucei and anti-Trypanosoma cruzi activities. In this work, we report the design and synthesis of pyrazolo[3,4-d]pyrimidine nucleosides with 3′- and 7-modifications and assess their potential as anti-Trypanosoma cruzi and antileishmanial agents. One compound was selected for in vivo evaluation in an acute Chagas disease mouse model.
1,3-disubstituted-4-aminopyrazolo [3, 4-d] pyrimidines, a new class of potent inhibitors for phospholipase D
Kulkarni, Aditya,Quang, Phong,Curry, Victoriana,Keyes, Renee,Zhou, Weihong,Cho, Hyejin,Baffoe, Jonathan,T?r?k, Béla,Stieglitz, Kimberly
, p. 270 - 281 (2014/10/15)
Phospholipase D enzymes cleave lipid substrates to produce phosphatidic acid, an important precursor for many essential cellular molecules. Phospholipase D is a target to modulate cancer-cell invasiveness. This study reports synthesis of a new class of phospholipase D inhibitors based on 1,3-disubstituted-4-amino-pyrazolopyrimidine core structure. These molecules were synthesized and used to perform initial screening for the inhibition of purified bacterial phospholipase D, which is highly homologous to the human PLD1. Initially tested with the bacterial phospholipase D enzyme, then confirmed with the recombinant human PLD1 and PLD2 enzymes, the molecules presented here exhibited inhibition of phospholipase D activity (IC50) in the low-nanomolar to low-micromolar range with both monomeric substrate diC4PC and phospholipid vesicles and micelles. The data strongly indicate that these inhibitory molecules directly block enzyme/vesicle substrate binding. Preliminary activity studies using recombinant human phospholipase Ds in in vivo cell assays measuring both transphosphatidylation and head-group cleavage indicate inhibition in the mid- to low-nanomolar range for these potent inhibitory novel molecules in a physiological environment. This study reports synthesis of a new class of PLD inhibitors based on 1,3-disubstituted-4-amino-pyrazolopyrimidine core structure. These molecules exhibited inhibition of human recombinant PLD activity (IC 50) in the low-nanomolar to low-micromolar range with monomeric substrate diC4PC and phospholipid vesicles and micelles. Preliminary activity studies using recombinant human PLDs in in vivo cell assays measuring both transphosphatidylation and head-group cleavage indicates inhibition in the mid- to low-nanomolar range for these potent inhibitory novel molecules in a physiological environment.
