Rational design and biological investigation of benzylidene-substituted pyrazolo[3,4- <i>b</i> ]pyridine derivatives as novel PIM-1 kinase inhibitors with anticancer potential

BACKGROUND: ]pyridine derivatives was designed and synthesized as potential PIM-1 kinase inhibitors with anticancer activity. METHODS: The novel derivatives were synthesized by a novel synthetic route involving a three-step synthetic method from 2-chloro-3-cyanopyridine to produce a total of ten derivatives 6A-6J. The structures of the novel derivatives were confirmed by Fourier Transform Infrared Spectroscopy (FT-IR), 1H and 13C Nuclear Magnetic Resonance Spectroscopy (NMR), and Mass Spectroscopy. The anticancer activity of the novel derivatives was assessed by evaluating their inhibitory activity against the MCF-7 human breast cancer cell line by a colorimetric MTT assay. The inhibitory activity of the novel derivatives against PIM-1 kinase was assessed by an enzyme-linked immunosorbent assay. The binding mode of the most active derivatives within the PIM-1 kinase active site was assessed by molecular docking studies. RESULTS: The results from this investigation revealed that some of the novel derivatives exhibited significant anticancer activity against the MCF-7 human breast cancer cell line. The most potent derivative 6H had an IC₅₀ value of 1.43 ± 0.18 μM, while compound 6D had an IC₅₀ value of 1.56 ± 0.30 μM compared to the standard drug doxorubicin. The inhibitory activity of the most active derivatives against PIM-1 kinase was concentration-dependent. The results from the molecular docking studies revealed that compound 6H had a favorable binding mode within the PIM-1 kinase active site by hydrogen bonding and hydrophobic interactions with some amino acid residues within the enzyme's active site. CONCLUSION: ]pyridine derivatives are potential anticancer agents that could be developed as potential anticancer drug candidates by inhibiting PIM-1 kinase activity.