Computational and experimental insights into azo-containing Aroylhydrazones: A promising class of CDK2 inhibitors

The discovery of novel small-molecule inhibitors targeting cyclin-dependent kinase 2 (CDK2) remains a critical area of research in drug development. Herein, five new azo-based aroylhydrazones (3a-e) were synthesized with high yields and thoroughly characterized using spectroscopic techniques. DFT calculations with the B3LYP functional and 6-311++G(d,p) basis set demonstrated a strong correlation between theoretical and experimental spectral data. Global reactivity assessments via HOMO-LUMO calculations identified 3e as the most electrophilic compound, while 3b displayed the highest hardness. ADMET evaluations confirmed that all synthesized compounds adhered to Lipinski's Rule of Five, suggesting favorable pharmacokinetic properties. Molecular docking studies against CDK2 revealed strong binding affinities, with the 3PXY-3c complex achieving an outstanding docking score of-10.7 kcal/mol and an MM/PBSA binding energy of-131.812 kJ/mol. To further explore its dynamic stability, a 100 ns MD simulation was performed for the 3PXY-3c complex. The results confirmed that 3c maintained stable interactions throughout the simulation, reinforcing its potential as a promising CDK2 inhibitor.