The development of new efficient therapeutics for the treatment of malaria and cancer is an important endeavor. Over the past 15 years, much attention has been paid to the synthesis of dimeric structures, which combine two units of artemisinin, as lead compounds of interest. A wide variety of atemisinin-derived dimers containing different linkers demonstrate improved properties compared to their parent compounds (e.g., circumventing multidrug resistance), making the dimerization concept highly compelling for development of efficient antimalarial and anticancer drugs. The present Perspective highlights recent developments on different types of artemisinin-derived dimers and their structural and functional features. Particular emphasis is put on the respective in vitro and in vivo studies, exploring the role of the length and nature of linkers on the activities of the dimers, and considering the future prospects of the dimerization concept for drug discovery.

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A series of hybrid compounds based on the natural products artemisinin and thymoquinone was synthesized and investigated for their biological activity against the malaria parasite 3D7 strain, human cytomegalovirus (HCMV), and two leukemia cell lines (drug-sensitive CCRF-CEM and multidrug-resistant subline CEM/ADR5000). An unprecedented one-pot method of selective formation of C-10α-acetate starting from a 1:1 mixture of C-10α- to C-10β-dihydroartemisinin was developed. The key step of this facile method is a mild decarboxylative activation of malonic acid mediated by DCC/DMAP. Ether-linked thymoquinone-artemisinin hybrids stood out as the most active compounds in all categories, while showing no toxic side effects toward healthy human foreskin fibroblasts and thus being selective. They exhibited EC values of 0.2 μM against the doxorubicin-sensitive as well as the multidrug-resistant leukemia cells and therefore can be regarded as superior to doxorubicin. Moreover, they showed to be five times more active than the standard drug ganciclovir and nearly eight times more active than artesunic acid against HCMV. In addition, hybrids possessed excellent antimalarial activity (EC = 5.9/3.7 nM), which was better than that of artesunic acid (EC = 8.2 nM) and chloroquine (EC = 9.8 nM). Overall, most of the presented thymoquinone-artemisinin-based hybrids exhibit an excellent and broad variety of biological activities (anticancer, antimalarial, and antiviral) combined with a low toxicity/high selectivity profile.