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.