A series of eighteen berberine derivatives were designed and synthesized via molecular hybridization, introducing boronic acid/ester pharmacophores at the C-9 position to improve the selectivity of the natural product against breast cancer. The in vitro antiproliferative activities against MDA-MB-468 and MCF-7 cell lines identified several promising leads. Notably, compounds 4c, 5d, 5f, and 8b demonstrated good activity coupled with high selectivity indices over the normal human embryonic kidney (HEK-293) cell line, outperforming berberine and 5-fluorouracil. Computational ADME profiling highlighted 8b and 5f as oral leads and 4c as a BBB-penetrant agent. Molecular docking provided a plausible hypothesis for a proteasome inhibition mechanism for 8b through interaction with the β5 subunit.
