New pyrazolopyridine and pyrazolothiazole-based compounds as anti-proliferative agents targeting c-Met kinase inhibition: design, synthesis, biological evaluation, and computational studies.

Abstract

c-Met tyrosine kinase plays a key role in the oncogenic process. Inhibition of the c-Met has emerged as an attractive target for human cancer treatment. This work deals with the design and synthesis of a new set of derivatives bearing pyrazolo[3,4-b]pyridine, pyrazolo[3,4-b]thieno[3,2-e]pyridine, and pyrazolo[3,4-d]thiazole-5-thione scaffolds, 5a,b, 8a-f, and 10a,b, respectively, utilizing 3-methyl-1-tosyl-1H-pyrazol-5(4H)-one (1) as a key starting material. All the new compounds were evaluated as antiproliferative agents against HepG-2, MCF-7, and HCT-116 human cancer cell lines utilizing 5-fluorouracil and erlotinib as two standard drugs. Compounds 5a,b and 10a,b represented the most promising cytotoxic activity of IC50 values ranging from 3.42 ± 1.31 to 17.16 ± 0.37 μM. Both 5a and 5b showed the most cytotoxicity and selectivity toward HepG-2, with IC50 values of 3.42 ± 1.31 μM and 3.56 ± 1.5 μM, respectively. The enzyme assay demonstrated that 5a and 5b had inhibition potency on c-Met with IC50 values in nanomolar range of 4.27 ± 0.31 and 7.95 ± 0.17 nM, respectively in comparison with the reference drug cabozantinib (IC50; 5.38 ± 0.35 nM). The impact of 5a on the cell cycle and apoptosis induction potential in HepG-2 and on the apoptotic parameters; Bax, Bcl-2, p53, and caspase-3 was also investigated. Finally, the molecular docking simulation of the most promising derivatives 5a and 5b was screened against c-Met to investigate the binding patterns of both compounds in the active site of the c-Met enzyme. In silico ADME studies were also performed for 5a and 5b to predict their physicochemical and pharmacokinetic characteristics.