Hydroxyurea, thiourea, and urea derivatives of coumarins: synthesis, characterization, molecular docking, DFT calculations, pharmacokinetics and anticancer potency

Abstract

The new Schiff bases (SB1-SB7) of hydroxyurea, thiourea, and urea with 3-acetylcoumarins have been synthesized and characterized by elemental analysis, ESI-HRMS, NMR, FT-IR, and UV-Vis spectroscopic techniques. The studied compounds show dose-dependent good-to-moderate anticancer efficacy. The MTT assay has been performed to determine in vitro cytotoxicity on human breast cancer (MCF-7) cells. The selective suppression of the MCF-7 cell line has been demonstrated by the synthesized compounds, with IC50 (in μg/mL) of SB1 (398.0), SB4 (354.8), SB3 (353.0), SB2 (298.2), SB6 (269.5), SB7 (166.7), and SB5 (157.9). The most potent compound, 1-hydroxy-3-[(1E)-1-(4-hydroxy-2-oxo-2H-chromen-3-yl)ethylidene]urea, (SB5) shows significant cytotoxicity with an IC50 value of 157.9 μg/mL against the tested cell line. The treated compound (SB5) shows a higher proportion of cells in G1 and S phases as (32.53%), and (19.77%) respectively, whereas a lower proportion of cells in G2 phase (31.25%) in comparison to the control (24.87% in G1, 15.27% in S, and 34.44% in G2). According to DFT analysis, the synthesized compounds have been found to show activity comparable to the standard drug, erlotinib. Likewise, the compounds interact well with the target protein (EGFR) through key amino acid residues with binding energies between –10.2 and –7.3 Kcal/mol and show the appropriate ADMET properties.