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

• Published in: European journal of medicinal chemistry 2019-08, Vol.175, p.2-19
• Main Authors: Umar, Tarana, Shalini, Shruti, Raza, Md Kausar, Gusain, Siddharth, Kumar, Jitendra, Seth, Prerna, Tiwari, Manisha, Hoda, Nasimul
• Format: Article
• Language: English
• Subjects: AChE inhibitors; Amyloid β aggregation inhibitors; Docking; N-(1H-pyrazolo[3,4-b]pyridin-3-yl)acetamides; Selectivity
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.04.038

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 (P1P9) 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. [Display omitted] •2-(piperazin-1-yl)-N-(1H-pyrazolo[3,4-b]pyridin-3-yl)acetamides are described as new multifunctional anti-Alzheimer’s agents.•They possess AChE and BChE inhibition, Aβ aggregation inhibition, Aβ disaggregation, antioxidation and metal-chelation properties.•The most potent molecule amongst the derivatives exhibited excellent anti-AChE activity with IC50 = 4.8 nM.•In vitro study revealed compounds to be capable of inhibiting self-induced β-amyloid aggregation with the highest inhibition percentage 81.65%.•Aβ1-42 aggregation was ascertained by TEM analysis.