896134-94-4

Upstream product

• 17672-27-4 4-hydrazinobenzonitrile 
• 123-06-8 Ethoxymethylenemalononitrile 

Downstream Products

• 896134-95-5 C₁₂H₈N₆ 

Relevant academic research and scientific papers

New pyrazolopyrimidine derivatives as Leishmania amazonensis arginase inhibitors

Arginase performs the first enzymatic step in polyamine biosynthesis in Leishmania and represents a promising target for drug development. Polyamines in Leishmania are involved in trypanothione synthesis, which neutralize the oxidative burst of reactive oxygen species (ROS) and nitric oxide (NO) that are produced by host macrophages to kill the parasite. In an attempt to synthesize arginase inhibitors, six 1-phenyl-1H-pyrazolo[3,4-d]pyrimidine derivatives with different substituents at the 4-position of the phenyl group were synthesized. All compounds were initially tested at 100 μM concentration against Leishmania amazonensis ARG (LaARG), showing inhibitory activity ranging from 36 to 74%. Two compounds, 1 (R=H) and 6 (R=CF3), showed arginase inhibition >70% and IC50 values of 12 μM and 47 μM, respectively. Thus, the kinetics of LaARG inhibition were analyzed for compounds 1 and 6 and revealed that these compounds inhibit the enzyme by an uncompetitive mechanism, showing Kis values, and dissociation constants for ternary complex enzyme-substrate-inhibitor, of 8.5 ± 0.9 μM and 29 ± 5 μM, respectively. Additionally, the molecular docking studies proposed that these two uncompetitive inhibitors interact with different LaARG binding sites, where compound 1 forms more H-bond interactions with the enzyme than compound 6. These compounds showed low activity against L. amazonensis free amastigotes obtained from mice lesions when assayed with as much as 30 μM. The maximum growth inhibition reached was between 20 and 30% after 48 h of incubation. These results suggest that this system can be promising for the design of potential antileishmanial compounds.

Synthesis, in vitro and in vivo anticancer activity of novel 1-(4-imino-1-substituted-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)urea derivatives

A series of pyrazolo[3,4-d]pyrimidine and urea hybrids have been designed, synthesized and evaluated for their anticancer activity in vitro and in vivo cancer models. Among them, compounds 28, 30, 33, 36 and 37 showed promising cytotoxicity against tested cancer cell lines. Compound 37 (CBS-1) appeared as the most active derivative and it exhibited better cytotoxicity against all tested cell lines as compared to doxorubicin. CBS-1 successfully inhibited cell cycle progression and displayed good apoptosis in A549 cells. CBS-1 significantly induced caspase-3 activation and suppressed NF-κB and IL-6 activation in immunocytochemistry, qPCR and western blot analysis. Additionally, CBS-1 prominently displayed tumoricidal effects in lung adenocarcinoma in vivo xenograft nude mice model.

Identification of novel GLUT inhibitors

The compound class of 1H-pyrazolo[3,4-d]pyrimidines was identified using HTS as very potent inhibitors of facilitated glucose transporter 1 (GLUT1). Extensive structure–activity relationship studies (SAR) of each ring system of the molecular framework was established revealing essential structural motives (i.e., ortho-methoxy substituted benzene, piperazine and pyrimidine). The selectivity against GLUT2 was excellent and initial in vitro and in vivo pharmacokinetic (PK) studies are encouraging.

Synthesis of N-aryl-5-amino-4-cyanopyrazole derivatives as potent xanthine oxidase inhibitors

Some pyrazolo[3,4-d]pyrimidines, structurally related with allopurinol, a well known xanthine oxidase inhibitor, clinically used in the therapy of gout, have also been reported as potent inhibitors of xanthine oxidase and the growth of several human tumour cell lines. Considering the potential interest of this family of compounds, the aim of the present study was to synthesise and provide a full chemical characterization of new N-aryl-5-amino-4-cyanopyrazole derivatives and their corresponding pyrazolo[3,4-d]pyrimidines. Their biological activity pertaining to the xanthine oxidase inhibition and effect on the growth of three tumour cell lines (MCF-7, NCI-H460, and SF-268) are also provided. With only one exception, the synthesised compounds showed no effect on the growth of the three tumour cell lines. However, a strong xanthine oxidase inhibitory activity was observed for almost all pyrazolo[3,4-d]pyrimidines tested, revealing some of them IC50 values below 1 μM. The results of the molecular docking studies of these compounds, against xanthine oxidoreductase are also described, providing an atomistic explanation of the differences in the inhibitory efficiency. MEP calculations were used to explain different inhibitory efficiency of similar inhibitors.