Synthesis of Artemisinin–Estrogen Hybrids Highly Active against HCMV, <i>P. falciparum</i>, and Cervical and Breast Cancer

Abstract

Artemisinin-estrogen hybrids were for the first time both synthesized and investigated for their <i>in vitro</i> biological activity against malaria parasites (<i>Plasmodium falciparum</i> 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 <b>8</b> (EC₅₀ = 3.8 nM) was about two times more active than its parent compound artesunic acid (<b>7</b>) (EC₅₀ = 8.9 nM) as well as the standard drug chloroquine (EC₅₀ = 9.8 nM) and was, therefore, comparable to the clinically used dihydroartemisinin (<b>6</b>) (EC₅₀ = 2.4 nM). Furthermore, hybrids <b>9</b>-<b>12</b> 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 (<b>7</b>) (EC₅₀ = 5.41 μM). These compounds also exerted a higher <i>in vitro</i> anti-HCMV efficacy than ganciclovir used as the standard of current antiviral treatment. In addition, hybrids <b>8</b>-<b>12</b> 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 <b>12</b>, exhibited submicromolar EC₅₀ values (0.15-0.93 μM) against breast cancer and C33A cell lines.