Cu(II)-Catalyzed Synthesis of Pyrazolo[3,4-<i>b</i>]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-<i>b</i>]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 (<i>m</i>/<i>z</i>) analyses. The compounds (<b>2a-l</b>) were screened for several in vitro and in silico activities. Compound <b>2g</b> showed impressive inhibitory activities against methicillin-resistant <i>Staphylococcus aureus</i> (MIC: 2 μg/mL), vancomycin-resistant Enterococci (MIC: 8 μg/mL), piperacillin-resistant <i>Pseudomonas aeruginosa</i>, and extended-spectrum beta-lactamase-producing <i>Escherichia coli</i> (MIC: 4 μg/mL) compared to the positive control, ciprofloxacin. Compared to standard doxorubicin, compound <b>2g</b> had a higher efficacy against the HepG2 cancer cell line, with a GI₅₀ value of 0.01 μM. The highly active compound <b>2g</b> was investigated for in silico molecular docking, density functional theory calculations (DFT), and SwissADME physicochemical properties. Compound <b>2g</b> had a higher docking score compared with standard (-8.5 vs -7.3 and -10.0 vs -8.4 kcal/mol). In compound <b>2g</b>, 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 <b>2g</b> exhibited promising antibacterial and cytotoxic activities.