Synthesis and anti-Cancer Activity of a New Hybrid Based Spirooxindole-Pyrrolidine -Thiochromene Scaffolds via [3 + 2] Cycloaddition Reaction: Computational Investigation

Abstract

A combined experimental and theoretical study of a newly synthesized cycloadduct of spirooxindole based thiochromene scaffold via [3 + 2] cycloaddition (32CA) reaction approach has been performed. The final adducts occurred via reaction of azomethine ylide (AY) with the ethylene derivative via ortho/endo 32CA protocol in respective regio- and diastereoselective fashion. In the light of the importance of intermolecular interactions in the crystal stability, Hirshfeld calculations were employed to predict all possible contacts affecting the molecular packing in the solid state of the studied systems. The results shed the light on the importance of O…H, F…H and H…C interactions as well as the π-π stacking interactions on the molecular packing. DFT calculations were used to compute the minimum energy structures and predict their electronic properties such as dipole moment, charge population and conceptual DFT reactivity descriptors. The ¹H- and ¹³C-NMR spectra of the studied systems were calculated and the resulting chemical shifts correlated very well with the experimental data (R²= 0.991-0.978). The anti-cancer activity of the synthesized spirooxindole based thiochromene motif was assessed and showed IC₅₀ of 8.34 ± 0.64, 11.25 ± 0.28, 16.0 ± 0.7, and 25.3 ± 0.25 µM against the four cancer cell lines MCF-7, MDA-MB231, PC3, and HeLa, respectively.

Graphical Abstract

Keywords:

• Spirooxindole
• Pyrrolidine
• Thiochromene
• [3 + 2] cycloaddition reaction (32CA)
• Azomethine ylide

Acknowledgments

The authors would like to extend their sincere appreciation to the Researchers Supporting Project (RSP-2021/64), King Saud University, Riyadh, Saudi Arabia, and project number PID2019-110776GB-I00 (AEI/FEDER, UE), Ministerio de Ciencias, Innovación y Universidades of the Spanish Government.

Disclosure statement

The authors declare no conflict of interest.

Author contributions

Conceptualization, A.B.; synthesis and characterization, M.A. and M.S.I.; A.M.K. and A.M.A.-M.; X-ray crystal structure was carried out by: M.H.; computational investigation: S.M.S.; L.R.D.; and Z.U-H.; writing—original manuscript, S.M.S. and A.B.; revision and editing, S.M.S.; L.R.D. and A.B. All authors have read and agreed to the published version of the manuscript.

Additional information

Funding

The authors would like to extend their sincere appreciation to the Researchers Supporting Project (RSP-2021/64), King Saud University, Riyadh, Saudi Arabia, and project number PID2019-110776GB-I00 (AEI/FEDER, UE), Ministerio de Ciencias, Innovación y Universidades of the Spanish Government.