Synthesis, computational study and cytotoxicity of 4-hydroxycoumarin-derived imines/enamines

In this study, we applied a direct condensation between 3-acetyl-4-hydroxy-2 H -chromen-2-one and different amines (anilines and benzyl amines) in order to synthesize some coumarin-based imines/enamines ( 3a – o ) as cytotoxic agents. All the compounds were characterized by means of FT-IR, NMR, mass spectroscopy and elemental analyses. Since the title compounds can exist as different forms including ( s - cis )-imine and ( s - trans )-imine or ( E and Z )-enamines, their conformational and geometrical aspects were investigated computationally by DFT method. The optimized geometry parameters, Δ E , Δ G , Δ H , Mulliken atomic charge, HOMO and LUMO energy, and NBO analysis suggested that these compounds can exist predominantly in ( E )-enamine form. All the synthesized compounds ( 3a – o ) were evaluated in vitro for their cytotoxic activities against cancer cell lines (MCF-7 and A549) and normal cell line (BEAS-2B) using the MTT assay. The 4-hydroxybenzyl derivative 3k was found to be the most potent cytotoxic agent with no selectivity, similar to doxorubicin. However, the 4-chlorobenzyl analog 3o could be considered as an equipotent compound respect to doxorubicin with higher selectivity. Graphic abstract