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

The new Schiff’s bases (SB1-SB7) of hydroxyurea, thiourea and urea with 3-acetylcoumarins were synthesized and characterized by elemental analysis, ESI-HRMS, NMR, FT-IR, UV-Vis, spectroscopic techniques. The studied compounds showed dose-dependent good-to-moderate anticancer efficacy. The MTT assay was performed for cytotoxicity in vitro on human breast cancer (MCF7) cells. The selective suppression of the MCF-7 cell line was 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)"  showed significant cytotoxicity with an IC50 value of 157.9 µg/mL against the tested cell line. The treated compound (SB5) showed a higher proportion of cells in G1 and G2 phases as (32.53%), and (31.25%) respectively whereas a lower proportion of cells in S phase (19.77%) compared to the control (24.87% in G1, 34.44 % in G2, and 15.27% in S). According to DFT analysis, the synthesized compounds were found reactive compared to standard drug, erlotinib, likewise, the compounds well interacted with target protein (EGFR) through key amino acid residues with binding energies, -10.2 — -7.3 Kcal/mol and showed the appropriate ADMET properties.