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 ()-7c displayed improved activity against artemisininresistant
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.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:85939 |
| Date | 09 June 2023 |
| Creators | von Bredow, Lukas, Schäfer, Thomas Martin, Hogenkamp, Julian, Tretbar, Maik, Stopper, Daniel, Kraft, Fabian B., Schliehe-Diecks, Julian, Schöler, Andrea, Borkhardt, Arndt, Bhatia, Sanil, Held, Jana, Hansen, Finn K. |
| Publisher | MDPI |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 333 |
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