An Unequivocal Synthesis of 2‐Aryl Substituted 3‐Amino‐2,4,5,7‐tetrahydro‐6<i>H</i>‐pyrazolo[3,4‐<i>b</i>]pyridin‐6‐ones

Bou‐Petit, Elisabeth; Picas, Elsa; Font-Bardı́a, Mercè; Ferrer, Nabí; Sempere, J.; Bellacasa, Raimon Puig de la; Batllori, Xavier; Teixidó, Jordi; Estrada‐Tejedor, Roger; Cajal, Santiago Ramón y; Borrell, José I.

doi:10.1002/slct.201700732

Cited by 4 publications

(2 citation statements)

References 8 publications

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“…These structures were obtained by the cyclization of 2-methoxy-6-oxo-1,4,5,6-tetrahydropyridin-3-carbonitriles ( S13 ), synthesized by the reaction of an α,β-unsaturated ester ( S12 ) and malononitrile in NaOMe/MeOH, with hydrazine or substituted hydrazines ( Figure S1B ). 40 We synthesized 37 compounds with a broad combination of substituents in the most interesting points of this scaffold (R2, R4, and R5). The compounds under study combined bulky and small substituents in the pyridone ring (H, Me, Ph, and substituted aromatic rings) and in the pyrazole ring (H, Me, Ph, substituted Ph and acyl groups) to explore the maximum number of possibilities (compounds S14a–g , S15a–x , and S16a–f ).…”

Section: Resultsmentioning

confidence: 99%

Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor

et al. 2022

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Targeting the kinases MNK1 and MNK2 has emerged as a valuable strategy in oncology. However, most of the advanced inhibitors are acting in an adenosine triphosphate (ATP)-competitive mode, precluding the evaluation of different binding modes in preclinical settings. Using rational design, we identified and validated the 4,6-diaryl-pyrazolo[3,4- b ]pyridin-3-amine scaffold as the core for MNK inhibitors. Signaling pathway analysis confirmed a direct effect of the hit compound EB1 on MNKs, and in line with the reported function of these kinases, EB1 only affects the growth of tumor but not normal cells. Molecular modeling revealed the binding of EB1 to the inactive conformation of MNK1 and the interaction with the specific DFD motif. This novel mode of action appears to be superior to the ATP-competitive inhibitors, which render the protein in a pseudo-active state. Overcoming this paradoxical activation of MNKs by EB1 represents therefore a promising starting point for the development of a novel generation of MNK inhibitors.

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Section: Resultsmentioning

confidence: 99%

Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor

et al. 2022

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“…The most commonly applied method for the preparation of pyrazolo[3,4- b ]pyridines uses 5-aminopyrazole as synthetic precursor [ 36 – 39 ]. Regardless to substantial studies in this field, researchers are still focused to provide convenient regioselective synthetic methods with mild conditions and good yields of the reactions [ 40 – 41 ].…”

Section: Reviewmentioning

confidence: 99%

5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines

Aggarwal

Kumar

2018

Beilstein J. Org. Chem.

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The condensation of 5-aminopyrazole with various bielectrophilic moieties results in the formation of pyrazoloazines, an interesting array of fused heterocyclic systems. The development of new synthetic routes towards pyrazoloazines for their biological and medicinal exploration is an attractive area for researchers throughout the world. The present review focuses on various synthetic methods developed in the last decade for the synthesis of differently substituted pyrazoloazines by a broad range of organic reactions by means of 5-aminopyrazole as a precursor. ReviewPyrazole and its derivatives are known to exhibit significant biological and pharmacological activities such as: anticancer [1,2], anti-inflammatory [3,4], antioxidant [5], antibacterial [6][7][8], analgesic [9], antiviral [10,11], antimicrobial [12,13], antifungal [6], antiglycemic [14], antiamoebic [15] and antidepressive [16,17]. Considering the immense biological properties pyrazole is one of the most widely studied nitrogen-containing heterocyclic nuclei. Fused pyrazole derivatives are composed of the pyrazole nucleus attached to other heterocyclic moieties which enable them to exhibit improved pharmacological activities compared to the isolated fragments. These compounds are currently used in several marketed drugs like cartazolate (1), zaleplon (2), sildenafil (3), allopurinol (4), indiplon (5), etazolate (6) etc. (Figure 1). Fused pyrazole derivatives, especially pyrazoloazines have been reported to mimic purine bases, present in DNA and RNA, due to close structural resemblance.In addition to the immense biological potential related to fused pyrazoles, their synthetic potential needs to be reviewed for further improvements and extension of interests. Various efforts have been developed for the synthesis of pyrazole-based fused heterocycles. 5-Aminopyrazoles have been extensively employed as useful synthons in designing and constructing a Beilstein J. Org. Chem. 2018, 14, 203-242. 204 A number of review articles have been published by us and others highlighting the synthetic and biological aspects of 5-aminopyrazoles [26][27][28] as well as on the synthesis of fused pyrazole derivatives [25]. However, a perusal of literature reveals that the importance of 5-aminopyrazoles as synthetic precursors for fused heterocycles has not been reported till now to the best of our knowledge. Recent literature shows resurgence of interest in the chemistry and bioactivity of 5-aminopyrazole derivatives leading to improvements in several already known reactions and syntheses of various fused heterocyclic derivatives with various biological activities. Considering the synthetic importance of 5-aminopyrazoles and synthesis of fused pyrazole derivatives with the need for a more general collection, herein we report an exhaustive overview of the main developments in the last decade in the chemistry of 5-aminopyrazoles for the design and synthesis of fused pyrazoloazines.The typical reactivity of 5-aminopyrazoles 5-Aminopyrazoles are polyfunctional co...

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Bicyclic 5-6 Systems: Three Heteroatoms 2:1

Sápi

Gérard

2022

Comprehensive Heterocyclic Chemistry IV

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An Unequivocal Synthesis of 2‐Aryl Substituted 3‐Amino‐2,4,5,7‐tetrahydro‐6H‐pyrazolo[3,4‐b]pyridin‐6‐ones

Cited by 4 publications

References 8 publications

Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor

Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor

5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines

Bicyclic 5-6 Systems: Three Heteroatoms 2:1

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