Synthesis of Artemisinin-Estrogen Hybrids Highly Active against HCMV, P. falciparum , and Cervical and Breast Cancer.

Artemisinin-estrogen hybrids were for the first time both synthesized and investigated for their in vitro biological activity against malaria parasites ( Plasmodium falciparum 3D7), human cytomegalovirus (HCMV), and a panel of human malignant cells of gynecological origin containing breast (MCF7, MDA-MB-231, MDA-MB-361, T47D) and cervical tumor cell lines (HeLa, SiHa, C33A). In terms of antimalarial efficacy, hybrid 8 (EC50 = 3.8 nM) was about two times more active than its parent compound artesunic acid ( 7 ) (EC50 = 8.9 nM) as well as the standard drug chloroquine (EC50 = 9.8 nM) and was, therefore, comparable to the clinically used dihydroartemisinin ( 6 ) (EC50 = 2.4 nM). Furthermore, hybrids 9 - 12 showed a strong antiviral effect with EC50 values in the submicromolar range (0.22-0.38 μM) and thus possess profoundly stronger anti-HCMV activity (approximately factor 25) than the parent compound artesunic acid ( 7 ) (EC50 = 5.41 μM). These compounds also exerted a higher in vitro anti-HCMV efficacy than ganciclovir used as the standard of current antiviral treatment. In addition, hybrids 8 - 12 elicited substantially more pronounced growth inhibiting action on all cancer cell lines than their parent compounds and the reference drug cisplatin. The most potent agent, hybrid 12 , exhibited submicromolar EC50 values (0.15-0.93 μM) against breast cancer and C33A cell lines.