To acquire matrine derivatives with enhanced anticancer activity, we designed and synthesized twenty-one 15-site matrine based isatohydrazone derivatives were designed and synthesized. The anti-proliferative activity of all the compounds against human cervical cancer cells (HeLa), human colon cancer cells (HCT116), and non-small cell lung cancer cells (A549) was examined by the MTT method. The majority of the compounds exhibited superior anticancer activity compared to matrine. Among them, compound 5a displayed the most potent anti-proliferative activity, with IC