Design and biological evaluation of imidazo[2,1-a]phthalazine compounds with antiproliferative properties in triple-negative breast cancer cells

Breast cancer is a worldwide burden issue, accounting for the most diagnosed cancer and the leading cause of cancer death among women. Significant progress has been made in its clinical management with the advent of personalized medicine, notably through pharmacogenomics, targeted therapies, and preventive measures. However, not all the patients benefit equally from these advances, as therapeutic outcomes largely depend on the breast cancer subtype. Triple-negative breast cancer (TNBC) is a highly aggressive subtype that poses substantial treatment challenges due to its resistance or poor responsiveness to both chemo- and hormone-based therapies. Here, we report the design, synthesis and evaluation of a novel series of 25 substituted imidazo[2,1- a ]phthalazines to assess their antiproliferative activity on breast cancer cell lines. Pharmacomodulation investigations identified compound 7i as particularly promising, displaying similar antiproliferative effects in both luminal A estrogen-dependent and TNBC cell lines (IC 50 at low micromolar ranges on MCF-7 and MDA-MB-231) and a strong anti-migration activity in TNBC cells (52% of inhibition on MDA-MB-231 at 10 μM). • Design, functionalization and solubility optimization of new imidazo[2,1- a ]phthalazine compounds with antiproliferative properties in triple-negative breast cancer cells. • Identification of compound 7i which displays improved water solubility and low micromolar antiproliferative activity against MDA-MB-231 cells. • Compound 7i exhibited low cytotoxicity towards MDA-MB-231 cells.