Abstract
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. Histone deacetylase inhibitors (HDACis) are an emerging new class of potential antiplasmodial drugs. In this work, we present the design, synthesis, and biological evaluation of a mini library of dihydroartemisinin–HDACi hybrid molecules. The screening of the hybrid molecules for their activity against selected human HDAC isoforms, asexual blood stage P. falciparum parasites, and a panel of leukemia cell lines delivered important structure–activity relationships. All synthesized compounds demonstrated potent activity against the 3D7 and Dd2 line of P. falciparum with IC50 values in the single-digit nanomolar range. Furthermore, the hybrid (α)-7c displayed improved activity against artemisinin-resistant parasites compared to dihydroartemisinin. 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. Taken together, this series of hybrid molecules represents an excellent starting point toward the development of antimalarial and antileukemia drug leads.
Highlights
The zinc-binding group (ZBG) chelates the Zn2+ ion in the active site of the enzymes, whereas the cap group engages the entrance area of the catalytic site. Both parts are connected by a suitable linker, which interacts with hydrophobic amino acids inside of the catalytic tunnel
In order to investigate the antiplasmodial properties of the synthesized DHA–Histone deacetylase inhibitors (HDACis) hybrids, all compounds were screened for their activity against the drug-sensitive 3D7 line of P. falciparum and the multidrug-resistant P. falciparum Dd2 line
We designed a mini library of DHA–HDACi hybrids, and the target compounds were synthesized from commercially available artemisinin using straightforward and efficient four- or five-step protocols
Summary
A wellknown strategy to identify new therapeutic agents is the “piggyback” approach focusing on drug targets that have been validated for other diseases. Pharmaceuticals 2022, 15, 333 research groups have identified histone deacetylase inhibitors (HDACis) as promising new antiplasmodial compounds [5,6]. Suitable synergistic effects between the respective targets can be addressed to circumvent drug resistance [17,21] With this complication being relevant in malaria therapy, polypharmacological. Cellular HDAC inhibitory activity was tested with a representative dihydroartemisinin-based HDACi. In vitro assays against the P. falciparum strains 3D7 and Dd2 demonstrated promising antiplasmodial potential with IC50 values ranging in the single-digit nanomolar concentration range. The most promising compounds were further tested for their ability to induce apoptosis in leukemia cells
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