One-step selective synthesis of benzofuran or hydroxyacetophenone derivatives with potential anticancer activity

We present in this work a direct, effective, and selective way to synthesize methylbenzofuran heterocycles or O-alkylated hydroxyacetophenone derivatives, with potential anticancer activity. The reaction pathway is one-step, is thermally controlled, and takes place both under microwave (MW) irradiation and conventional thermal heating (TH). Under MW irradiation, the reactions have certain benefits in terms of better yields, significantly reduced solvent consumption and reaction time, decreased energy consumption, and could be considered environmentally friendly. All 25 benzofuran derivatives and their intermediates were tested against 55 cancer cell lines at a single concentration of 10 μM. The anticancer assay revealed that the O-alkylated hydroxyacetophenones are more active compared to methylbenzofurans, with a very good lethality against the majority of the 55 tested cell lines. Among the tested compounds, the hydroxyacetophenones 3aa and 3cb demonstrated the best anticancer profile and were subjected to the subsequent five-dose antiproliferative assay. These compounds were active at low micromolar concentrations against the leukemia SR cell line, the breast cancer MDA-MB-468 cell line, the melanoma MDA-MB-435 cell line, and the colon cancer HCT-15 cell line. QSAR simulations of the ADMET properties of the compounds showed promising drug-like profiles for 3aa and 3cb, with very good selectivity for tumor cells and good physicochemical properties. The in-silico ADMET study predicted high gastrointestinal absorption, moderate to high water solubility, and good oral bioavailability for the tested compounds. The in-silico molecular docking studies indicate VEGFR-2 and CSF1R as possible binding sites for our compounds.