Cu(II)-Catalyzed Synthesis of Pyrazolo[3,4-b]pyridine Derivatives and Their Potential Antibacterial and Cytotoxic Activities with Molecular Docking, DFT Calculation, and SwissADME Analysis.

The present work focuses on a newly synthesized pyrazolo[3,4-b]pyridine prepared by formal [3 + 3] cycloaddition using copper(II) acetylacetonate as the catalyst; efficient and effective mild reactions with high yields were obtained using this method. The synthesized compounds were identified by FT-IR, ¹H and ¹³C NMR, and mass spectra (m/z) analyses. The compounds (2a-l) were screened for several in vitro and in silico activities. Compound 2g showed impressive inhibitory activities against methicillin-resistant Staphylococcus aureus (MIC: 2 μg/mL), vancomycin-resistant Enterococci (MIC: 8 μg/mL), piperacillin-resistant Pseudomonas aeruginosa, and extended-spectrum beta-lactamase-producing Escherichia coli (MIC: 4 μg/mL) compared to the positive control, ciprofloxacin. Compared to standard doxorubicin, compound 2g had a higher efficacy against the HepG2 cancer cell line, with a GI₅₀ value of 0.01 μM. The highly active compound 2g was investigated for in silico molecular docking, density functional theory calculations (DFT), and SwissADME physicochemical properties. Compound 2g had a higher docking score compared with standard (-8.5 vs -7.3 and -10.0 vs -8.4 kcal/mol). In compound 2g, the energy gap was 0.17 eV, as determined by using DFT calculations. The physicochemical properties of all compounds were investigated by using SwissADME. Overall, compound 2g exhibited promising antibacterial and cytotoxic activities.