Visible-light promoted catalyst-free (VLCF) multi-component synthesis of spiro indolo-quinazolinone-pyrrolo[3,4-a]pyrrolizine hybrids: evaluation of in vitro anticancer activity, molecular docking, MD simulation and DFT studies

Abstract

A new and highly efficient visible-light-promoted catalyst free (VLCF) strategy for neat and clean synthesis of spiro indolo-quinazolinone-pyrrolo[3,4-a]pyrrolizine hybrids (6a–d) has been introduced. We have performed visible-light triggered 1,3-Dipolar cycloaddition reaction of maleimide (5a–d) with azomethine ylide generated in situ derived from tryptanthrin (3) and L-proline (4) to obtain desired products (6a–d) in good to excellent yield. Authentication and characterization of product was done using various spectroscopic techniques such as IR, ¹H NMR, ¹³C NMR, Mass spectrometry and single crystal XRD analysis. To explain the reaction spontaneity, product stability, reactivity as well as possible mode of the interaction a quantum chemical investigation was performed and depicted through DFT studies. The synthesized compound 6a was also evaluated for anti-proliferative activity against a panel of five cancer cell lines (MCF-7, MDA-MB-231, HeLa, PC-3 and Ishikawa) and normal human embryonic kidney (HEK-293) cell line by using MTT assay. Compound 6a showed very good in vitro anti-proliferative activity (IC₅₀  = 6.58–17.98 μM) against four cancer cell lines and no cytotoxicity against normal HEK-293. In order to evaluate the anticancer potential of compounds 6a-d, molecular docking was performed against wild type and mutant EGFR. The results suggest that all the compounds occupied the active site of both enzymes, with a strong binding energy (−10.2 to −11.5 kcal/mol). These results have been confirmed by molecular dynamics simulation by evaluating root mean square deviation (RMSD) and root mean square fluctuation (RMSF), along with principal component analysis (PCA).

Communicated by Ramaswamy H. Sarma

Keywords:

• visible-light catalyst-free (VLCF)
• EDA complex
• azomethine ylide
• spiro-fused
• anticancer
• DFT study
• molecular docking
• MD simulation
• environment-friendly

Acknowledgements

The authors acknowledge the UGC, New Delhi, India for providing financial support. We also acknowledge USIF, AMU and IIT, Ropar for helping us with analytical facilities. We are grateful to the Chairman of Department of Chemistry, AMU, Aligarh, for providing basic infrastructures and necessary facilities for to carry out our research.

Disclosure statement

There is no conflict of interest among the authors.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.