Synthesis and in vitro antiproliferative activity of certain novel pyrazolopyridines with potential p38α MAPK‐inhibitory activity

• Published in: Archiv der Pharmazie (Weinheim) 2022-02, Vol.355 (2)
• Main Authors: Farahat, Aya A, Samir, Eman M, Zaki, Mayssoune Y, Serya, Rabah A T, Hatem A Abdel‐Aziz
• Format: Article
• Language: English
• Subjects: Apoptosis; Cell cycle; Kinases
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.202100302

Novel series of pyrazolo[3,4‐b]pyridines 9a–j and 14a–f were prepared via a one‐pot three‐component reaction. Compounds 9a–j were synthesized by the reaction of 3‐(4‐chlorophenyl)−1‐phenyl‐1H‐pyrazol‐5‐amine (4) with benzoyl acetonitriles 3a,b and aldehydes 5a–e, whereas the spiro derivatives 14a–f were synthesized by the reaction of pyrazole derivative 4 with 3a–c and indoline‐2,3‐diones 10a,b. Screening of the antiproliferative activity of 9a–j and 14a–f revealed that 14a and 14d were the most potent analogues against HepG2 and HeLa cells, with IC50 = 4.2 and 5.9 μM, respectively. Moreover, compounds 9c and 14a could promote cell cycle disturbance and apoptosis in HepG2 cells, as evidenced by DNA flow cytometry and Annexin V‐FITC/PI assays. Cell cycle analysis of 9c and 14a indicated a reduction in HepG2 cells in the G1 phase, with arrest in the S phase and the G2/M phase, respectively. Also, 9c and 14a are good apoptotic inducers in the HepG2 cell line. Furthermore, compounds 9h and 14d stood out as the most efficient antiproliferative agents in the NCI 60‐cell line panel screening, with mean GI % equal to 60.3% and 55.4%, respectively. Additionally, 9c, 9h, 14a, and 14d showed good inhibitory action against the cellular pathway regulator p38α kinase, with IC50 = 0.42, 0.41, 0.13, and 0.64 μM, respectively. A docking study was carried out on the p38α kinase active site, showing a binding mode comparable to that of reported p38 mitogen‐activated protein kinase inhibitors. These newly discovered pyrazolo[3,4‐b]pyridines could be considered as potential candidates for the development of newly targeted anticancer agents.