Synthesis, in vitro evaluation, and SAR studies of a potential antichagasic 1H-pyrazolo[3,4-b]pyridine series

Dias, Luiza R.S.; Santos, Marcelo Bannwart; Albuquerque, Sérgio de; Castro, Helena C.; Souza, Alessandra Mendonça Teles de; Freitas, A. C. C.; DiVaio, Maria A.V.; Cabral, Lúcio Mendes; Rodrigues, Carlos Rangel

doi:10.1016/j.bmc.2006.09.067

Cited by 73 publications

(17 citation statements)

References 10 publications

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“…It is important to notice that the toxicity predicted herein does not guarantee that these compounds are completely free of any toxic effect but reinforces their promising antiplatelet profile 13) (Fig. 4).…”

Section: Theoretical Analysismentioning

confidence: 81%

“…Thus, international efforts are now being made to develop new antiplatelets agents with low collateral effects [9][10][11][12] . We have recently reported an efficient method for the synthesis of N '-substituted-phenylmethylene-1H-pyrazolo [3,4-b]pyridine-carbohydrazides 3a, 3c, 3f and 3h compounds by a sequence of 3 reactions from 5-amino-3-methyl-1-phenyl-1H-pyrazole 13) . In order to identify the leading compound for developing new antiplatelet agents, and treat thrombotic diseases, we report here seven new pyrazolopiridine derivatives 3b, 3d, 3e, 3g, 3i, 3j and 3k.…”

Section: Introductionmentioning

confidence: 99%

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Antiplatelet activity and structure-activity relationship study of Pyrazolopyridine Derivatives as potential series for treating thrombotic diseases

Geraldo

Bello

Dias

et al. 2010

JAT

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Aim: Platelets plays a central role in hemostatic processes and consequently are similarly involved in pathological processes, such as arterial thrombosis and atherosclerosis. Herein we described the synthesis, antiplatelet profile and structure-activity relationship (SAR) of a new series of N '-substitutedphenylmethylene-1H-pyrazolo[3,4-b]pyridine-carbohydrazide derivatives (3a-3k). Methods: These compounds were synthesized in good yield and tested in platelet aggregation assays using collagen, ADP and arachidonic acid as agonists. We also performed a SAR studies using SPAR-TAN' 08 program, in silico ADMET screening and the Lipinski "rule of five" using Osiris Property Explorer and molinspiration on-line programs. Results: Interestingly, the new compounds were active against collagen and arachidonic acid (AA) with the two most actives compounds (3a and 3c -IC50 61 M and 68 M respectively) almost 5-fold more potent than aspirin (IC50 300 M). These derivatives showed low theoretical toxicity risks in in silico ADMET screening and fulfilled the Lipinski rule of five, suggesting good oral biodisponibility. Conclusion: This work showed carbohydrazide group as potential for designing new antiplatelets. On that purpose, 3a and 3c may act as prototypes to generate more efficient and safe molecules for treating thrombotic diseases. J Atheroscler Thromb, 2010; 17:730-739.

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Section: Theoretical Analysismentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Antiplatelet activity and structure-activity relationship study of Pyrazolopyridine Derivatives as potential series for treating thrombotic diseases

Geraldo

Bello

Dias

et al. 2010

JAT

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“…They present a significant therapeutic potential including antimicrobial 9 , antichagasic 10 , analgesic 11 , anti-tumor 12 and antithrombotic activities 13 . Previously, N 0 -substituted-phenylmethylene-3-methyl-1,6-diphenyl-1H-pyrazolo [3,4-b]pyridine-4-carbohydrazide derivatives with antihemostatic profile have been synthesized and their chemical structures were characterized by our group (Table 2) 8,14 . The hit molecules previously found were shown to successfully inhibit platelet aggregation in rabbit platelet-rich plasma (PRP) using ARA as a proaggregant stimuli, highlighting compound 3a, whose potency (IC 50 ¼61 mM) was nearly five times better than ASA versus (IC 50 ¼300 mM).…”

Section: Introductionmentioning

confidence: 99%

“…The Chemical Abstracts Service (CAS) register numbers of these compounds, previously described 8,14 , are 917369-16-5 (3a), 1340493-99-3 (3b), 1340493-48-2 (3d), 917369-21-2 (3h) and 1340494-21-4 (3j). Therefore, we evaluated their inhibition profile on human platelet aggregation against six different inducers (ARA, Collagen, ADP and Epinephrine, thrombin and the thromboxane receptor agonist U-44619).…”

Section: Introductionmentioning

confidence: 99%

Antiplatelet pyrazolopyridines derivatives: pharmacological, biochemical and toxicological characterization

Saito

Lourenço

Dias

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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Platelet aggregation is one of the main events involved in vascular thrombus formation. Recently, N 0 -substituted-phenylmethylene-3-methyl-1,6-diphenyl-1H-pyrazolo [3,4-b]pyridine-4-carbohydrazides were described as antiplatelet derivatives. In this work, we explore the properties of these antiplatelet agents through a series of pharmacological, biochemical and toxicological studies. The antiplatelet activity of each derivative was confirmed as 3a, 3b and 3 h significantly inhibited human platelet aggregation induced by arachidonic acid, with no detectable effect on clotting factors or healthy erythrocytes. Importantly, mice treated with derivative 3a showed a higher survival rate at an in vivo model of pulmonary thromboembolism with a lower bleeding risk in comparison to aspirin. The in silico studies pointed a series of structural parameters related to thromboxane synthase (TXS) inhibition by 3a, which was confirmed by tracking plasma levels of PGE 2 and TXB 2 through an in vitro enzyme immunoassay. Derivative 3a showed selective TXS inhibition allied with low bleeding risk and increased animal survival, revealing the derivative as a promising candidate for treatment of cardiovascular diseases.

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“…Os intermediários reduzidos não sofrem "redox cycling", Adicionalmente, tem sido reportado que a diferença de energia entre os orbitais de fronteira (GAP = E LUMO -E HOMO ) está associada com a atividade tripanocida em compostos derivados do pirazolo-piridina e 5-etenilbenzofuroxano [248,249] . De acordo com essas publicações, quanto menor for os valores de GAP, maior é a afinidade eletrônica dos grupos eletrofílicos, como é o caso do grupamento NO 2 , e conseqüentemente mais ativos são os compostos [248,249] . O valor de GAP otimizado através de DFT na fase aquosa para o pacientes e comumente usada em experimentos pré-clínicos [243] .…”

Section: Atividade Anti-t Cruzi In Vivounclassified

Tetraaminas de rutênio (II) como transportadoras de óxido nítrico e benznidazol e sua ação sobre o Trypanosoma cruzi

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Synthesis, in vitro evaluation, and SAR studies of a potential antichagasic 1H-pyrazolo[3,4-b]pyridine series

Cited by 73 publications

References 10 publications

Antiplatelet activity and structure-activity relationship study of Pyrazolopyridine Derivatives as potential series for treating thrombotic diseases

Antiplatelet activity and structure-activity relationship study of Pyrazolopyridine Derivatives as potential series for treating thrombotic diseases

Antiplatelet pyrazolopyridines derivatives: pharmacological, biochemical and toxicological characterization

Tetraaminas de rutênio (II) como transportadoras de óxido nítrico e benznidazol e sua ação sobre o Trypanosoma cruzi

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