Design, synthesis, molecular modeling and biological evaluation of novel 1H-pyrazolo[3,4-b]pyridine derivatives as potential anticancer agents

• Fifteen compounds of novel 1H-pyrazolo [3,4-b]pyridine derivatives were designed and synthesized.
• Molecular docking was carried out against DNA.
• In vitro anti-proliferative activity against HePG-2, MCF-7, HCT-116, and PC-3 cell lines, DNA binding affinity and association constants assay were carried out.
• A strong relationship exists between the anticancer activity and the DNA binding activity.

In trying to develop new anticancer agents, a series of 1H-pyrazolo[3,4-b]pyridine derivatives was designed and synthesized. Fifteen compounds were evaluated in vitro for their anti-proliferative activity against HePG-2, MCF-7, HCT-116, and PC-3 cell lines. Additionally, DNA binding affinity of the synthesized derivatives was investigated as a potential mechanism for the anticancer activity using DNA/methyl green assay and association constants assay. Compounds 19, 20, 21, 24 and 25 exhibited good activity against the four cancer cells comparable to that of doxorubicin. Interestingly, DNA binding assay results were in agreement with that of the cytotoxicity assays where the most potent anticancer compounds showed good DNA binding affinity comparable to that of doxorubicin and daunorubicin. Furthermore, a molecular docking of the tested compounds was carried out to investigate their binding pattern with the prospective target, DNA (PDB-code: 152d).

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