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von Bredow, Lukas [Author]; Schäfer, Thomas Martin [Author]; Hogenkamp, Julian [Author]; Tretbar, Maik [Author]; Stopper, Daniel [Author]; Kraft, Fabian B. [Author]; Schliehe-Diecks, Julian [Author]; Schöler, Andrea [Author]; Borkhardt, Arndt [Author]; Bhatia, Sanil [Author]; Held, Jana [Author]; Hansen, Finn K. [Author]

Synthesis, Antiplasmodial, and Antileukemia Activity of Dihydroartemisinin–HDAC Inhibitor Hybrids as Multitarget Drugs

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  • Media type: E-Article
  • Title: Synthesis, Antiplasmodial, and Antileukemia Activity of Dihydroartemisinin–HDAC Inhibitor Hybrids as Multitarget Drugs
  • Contributor: von Bredow, Lukas [Author]; Schäfer, Thomas Martin [Author]; Hogenkamp, Julian [Author]; Tretbar, Maik [Author]; Stopper, Daniel [Author]; Kraft, Fabian B. [Author]; Schliehe-Diecks, Julian [Author]; Schöler, Andrea [Author]; Borkhardt, Arndt [Author]; Bhatia, Sanil [Author]; Held, Jana [Author]; Hansen, Finn K. [Author]
  • Published: Basel: MDPI, [2023]
  • Published in: Pharmaceuticals ; 15, (2022)
  • Language: English
  • Keywords: histone deacetylase ; multitarget drugs ; artemisinin
  • Origination:
  • Footnote:
  • Description: Artemisinin-based combination therapies (ACTs) are the gold standard for the treatment ofmalaria, but the efficacy is threatened by the development of parasite resistance. Histone deacetylaseinhibitors (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 selectedhuman HDAC isoforms, asexual blood stage P. falciparum parasites, and a panel of leukemia celllines delivered important structure–activity relationships. All synthesized compounds demonstratedpotent activity against the 3D7 and Dd2 line of P. falciparum with IC50 values in the single-digitnanomolar range. Furthermore, the hybrid ()-7c displayed improved activity against artemisininresistantparasites compared to dihydroartemisinin. The screening of the compounds against five celllines from different leukemia entities revealed that all hydroxamate-based hybrids (7a–e) and theortho-aminoanilide 8 exceeded the antiproliferative activity of dihydroartemisinin in four out of fivecell lines. Taken together, this series of hybrid molecules represents an excellent starting point towardthe development of antimalarial and antileukemia drug leads.
  • Access State: Open Access
  • Rights information: Attribution (CC BY)