An increasing number of artemisinin (ARS) and its derivatives have been reported for their potential therapeutic value of human cancer. However, their therapeutic potencies are limited owing to their poor pharmacokinetic profiles. Our previous studies showed that a lead compound ARS4 originated from incorporating the pharmacophore of the approved chemotherapeutic agent melphalan into the basic skeleton of artemisinin with a succinic linker exhibited an excellent toxicity to human ovarian cancer cells and low cytotoxicity to normal cells. The mechanism studies demonstrated that it inhibited the growth and proliferation of ovarian cancer cells and resulted in S-phase arrest, apoptosis and inhibition of migration. Meanwhile, it exhibited excellent antitumor activities in animal models. Herein, further structure optimization for this lead compound ARS4 was performed and nineteen novel derivatives were designed and synthesized. Among them, compounds 10-12, 15, 16, 18 and 19 demonstrated powerful cytotoxic effects against human liver cancer and ovarian cancer cell lines, with their IC_50s below 0.86 μM against Hep3B and A2780 cell lines, which are superior to that of ARS4. Four compounds (11, 15, 16 and 18) were selected to further evaluate their antitumor activities in in vitro and in vivo ovarian and liver cancer models, the results indicated that compound 18 exhibited the best therapeutic effect, not only effectively inhibited the growth of 7404 xenograft and Huh7 xenograft, but also presented a good dose-dependent inhibition toward the growth of A2780 xenograft. Overall, based on these positive results, these novel chemical structures may provide a new inspiration for the discovery of novel antitumor agents originated from artemisinin scaffolds.