Synthesis, crystal structure, Hirshfeld surface, computational and biological studies of spiro-oxindole derivatives as MDM2-p53 inhibitors

The spiro-oxindole derivatives were synthesized via a 1,3-dipolar cycloaddition approach and characterized by FT-IR, ¹H, ¹³C NMR and mass spectral techniques. The single crystal XRD of 6d further validates the formation of compounds. DFT calculations indicated the reactive nature of compound 6d. Docking studies with 5LAW disclosed the minimum binding energy of - 10.83 kcal/mol for 6d. Furthermore, safe oral bioavailability was ensured by the physicochemical, pharmacokinetic, and toxicity predictions. The Anticancer analysis of synthesized compounds showed substantial activity against A549 cells, notably with an IC₅₀ value of 8.13 ± 0.66 µM for 6d compared to standard doxorubicin. 6d was also evaluated for cytotoxicity against L929 healthy cells and A549, showing selectivity towards A549 than healthy cells. AO/EB staining method showed early apoptotic cellular death in the A549 cell line in a dose-dependent manner.

ADMET; Apoptosis; DFT; Docking; Hirshfeld surface analysis; MDM2-p53 inhibitor; Single crystal XRD.