Typically designed by merging two pharmacophores into a single molecule, such compounds offer the advantage of a more predictable metabolic behavior and simultaneous occupation of each target. A promising alternative is the concept of polypharmacology, which aims to serve two individual modes of action using only one drug. One benefit of such drug cocktails is the possibility of suppressing resistance-driving mechanisms, but due to different pharmacokinetic profiles and possible unwanted drug-drug interactions, the scope of combination therapies may turn out to be limited. Using two or more separate drugs, combination therapies are effective for the treatment of complex diseases, such as malaria, cancer, HIV, or tuberculosis. falciparum, HDACis have also shown potential as antimalarial drugs in the preclinical stage. With five HDAC isoforms being prevalent in P. Impacting the acetylation levels of histones and other substrates, HDACs control the transcriptional regulation of genes in eukaryotes and have thus become valuable targets in cancer therapy. Using this method, multiple research groups have identified histone deacetylase inhibitors (HDACis) as promising new antiplasmodial compounds. A well-known strategy to identify new therapeutic agents is the “piggyback” approach focusing on drug targets that have been validated for other diseases. To avoid cross-resistance, new antimalarials should engage in novel modes of action that are capable of targeting the parasite at different life cycle stages. Artemisinin-based combination therapies (ACTs) are the current gold standard of malaria treatments, but the rapid development of drug resistance remains an issue to be tackled by new therapeutic approaches. In 2019, it accounted for 409,000 deaths among a total of 229 million cases, most of which were caused by P. Malaria is a tropical disease caused by different species of the Plasmodium genus.

Taken together, this series of hybrid molecules represents an excellent starting point toward the development of antimalarial and antileukemia drug leads.

The screening of the compounds against five cell lines from different leukemia entities revealed that all hydroxamate-based hybrids ( 7a–e) and the ortho-aminoanilide 8 exceeded the antiproliferative activity of dihydroartemisinin in four out of five cell lines. Furthermore, the hybrid (α)- 7c displayed improved activity against artemisinin-resistant parasites compared to dihydroartemisinin. falciparum with IC 50 values in the single-digit nanomolar range. All synthesized compounds demonstrated potent activity against the 3D7 and Dd2 line of P. falciparum parasites, and a panel of leukemia cell lines delivered important structure–activity relationships. The screening of the hybrid molecules for their activity against selected human HDAC isoforms, asexual blood stage P. In this work, we present the design, synthesis, and biological evaluation of a mini library of dihydroartemisinin–HDACi hybrid molecules. Histone deacetylase inhibitors (HDACis) are an emerging new class of potential antiplasmodial drugs. Artemisinin-based combination therapies (ACTs) are the gold standard for the treatment of malaria, but the efficacy is threatened by the development of parasite resistance.

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