Design, synthesis, and biological evaluation with molecular dynamics study of novel pyrazolo[3,4-d]pyrimidine derivatives as anti-cancer agents.

In continuation of our efforts to discover new structural chemotypes with significant chemotherapeutic activities, a novel series of pyrazolo[3,4-d]pyrimidine-based compounds linked to a piperazine ring, bearing different aromatic moieties, through different linkages was designed and synthesized as FLT3 inhibitors. All of the newly synthesized compounds were evaluated for their cytotoxicity on 60-NCI cell lines. Compounds with the piperazine acetamide linkage XIIa-f & XVI exhibited a remarkable anticancer activity among all of the tested compounds, especially against non-small cell lung cancer, melanoma, leukemia and renal cancer models. Furthermore, compound XVI (NSC no - 833644) was further screened with a 5-dose assay on nine subpanels and exhibited a GI(50) between 1.17 and 18.40 μM. On the other hand, molecular docking and dynamics studies were performed to predict the binding mode of the newly synthesized compounds in the FLT3 binding domain. Finally, through a predictive kinetic study, several ADME descriptors were calculated.