6752-16-5Relevant articles and documents
Exploration of nitrogen heterocycle scaffolds for the development of potent human neutrophil elastase inhibitors
Cantini, Niccolò,Khlebnikov, Andrei I.,Crocetti, Letizia,Schepetkin, Igor A.,Floresta, Giuseppe,Guerrini, Gabriella,Vergelli, Claudia,Bartolucci, Gianluca,Quinn, Mark T.,Giovannoni, Maria Paola
, (2020/11/25)
Human neutrophil elastase (HNE) is a potent protease that plays an important physiological role in many processes but is also involved in a variety of pathologies that affect the pulmonary system. Thus, compounds able to inhibit HNE proteolytic activity could represent effective therapeutics. We present here a new series of pyrazolopyridine and pyrrolopyridine derivatives as HNE inhibitors designed as modifications of our previously synthesized indazoles and indoles in order to evaluate effects of the change in position of the nitrogen and/or the insertion of an additional nitrogen in the scaffolds on biological activity and chemical stability. We obtained potent HNE inhibitors with IC50 values in the low nanomolar range (10–50 nM), and some compounds exhibited improved chemical stability in phosphate buffer (t1/2 > 6 h). Molecular modeling studies demonstrated that inhibitory activity was strictly dependent on the formation of a Michaelis complex between the OH group of HNE Ser195 and the carbonyl carbon of the inhibitor. Moreover, in silico ADMET calculations predicted that most of the new compounds would be optimally absorbed, distributed, metabolized, and excreted. Thus, these new and potent HNE inhibitors represent novel leads for future therapeutic development.
A multifunctional therapeutic approach: Synthesis, biological evaluation, crystal structure and molecular docking of diversified 1H-pyrazolo[3,4-b]pyridine derivatives against Alzheimer's disease
Umar, Tarana,Shalini, Shruti,Raza, Md Kausar,Gusain, Siddharth,Kumar, Jitendra,Seth, Prerna,Tiwari, Manisha,Hoda, Nasimul
, p. 2 - 19 (2019/05/06)
2-(piperazin-1-yl)–N-(1H-pyrazolo[3,4-b]pyridin-3-yl)acetamides are described as a new class of selective and potent acetylcholinesterase (AChE) inhibitors and amyloid β aggregation inhibitors. Formation of synthesized compounds (P1–P9) was justified via H1 NMR, C13 NMR, mass spectra and single crystal X-Ray diffraction study. All compounds were evaluated for their acetylcholinesterase and butyrylcholinesterase inhibitory activity, inhibition of self-mediated Aβ aggregation and Cu(II)-mediated Aβ aggregation. Also, docking study carried out was in concordance with in vitro results. The most potent molecule amongst the derivatives exhibited excellent anti-AChE activity (IC50 = 4.8 nM). Kinetic study of P3 suggested it to be a mixed type inhibitor. In vitro study revealed that all the compounds are capable of inhibiting self-induced β-amyloid (Aβ) aggregation with the highest inhibition percentage to be 81.65%. Potency of P1 and P3 to inhibit self-induced Aβ1-42 aggregation was ascertained by TEM analysis. Compounds were also evaluated for their Aβ disaggregation, antioxidation, metal-chelation activity.
Use of 3-(trifluoromethyl)-1H-pyrazolo-[3,4-b]pyridine as a versatile building block
Schirok, Hartmut,Griebenow, Nils,Fürstner, Chantal,Dilmac, Alicia M.
, p. 5597 - 5601 (2015/08/03)
A one-pot multigram synthesis of 3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine starting from 2-fluoropyridine using directed ortho metallation (DoM) technique is described. The compound contains an anionically activatable trifluoromethyl group and is a versatile building block for the microwave assisted synthesis of 3-substituted 1H-pyrazolo[3,4-b]pyridines.
