Coumarin-Maleimide Hybrids: Design, Synthesis, Cytotoxic Activities, and Molecular Docking

A series of amino derivatives of coumarin-maleimide hybrid compounds was synthesized, beginning with 7-amino-4-methylcoumarin. This compound reacts with 2,3-dichloromaleic anhydride to produce the corresponding 3,4-dichloromaleimide. By substituting the chlorine atom with various secondary or aromatic amines, a collection of 3-amino-4-chloromaleimides was obtained. Nineteen coumarin-maleimide hybrid compounds were tested for cytotoxicity against three cancer cell lines a breast cancer cell line (T47D), a cervical cancer cell line (HeLa), and a lung cancer cell line (A549), in addition to a normal monkey kidney cell line (VERO). Among these compounds, compound <b>3t</b> exhibited the highest activity against the breast cancer cells (T47D, IC50 = 5.5 µM), surpassing the positive control doxorubicin (IC50 = 7.36 µM), followed by compounds <b>3p</b>, <b>3n</b>, and <b>3r</b>, all of which demonstrated good IC50 values. In contrast, compounds <b>3c</b>, <b>3a</b>, and <b>3p</b> exhibited the greatest activity against the lung cancer cell line. Notably, all compounds showed no toxicity against the normal VERO cells. Molecular docking studies indicated that compound <b>3t</b> has an excellent binding affinity for two proteins: the human estrogen receptor alpha (hER) and the progesterone receptor (PR).