Journal
PHARMACEUTICALS
Volume 15, Issue 3, Pages -Publisher
MDPI
DOI: 10.3390/ph15030333
Keywords
histone deacetylase; artemisinin; multitarget drugs
Categories
Funding
- Deutsche Forschungsgemeinschaft (DFG) [HA 7783/1-2, HE 7607/1-2]
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [270650915, GRK 2158]
- Lowenstern e.V.
- Katharina-Hardt Foundation
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This study presents the design, synthesis, and biological evaluation of a mini library of dihydroartemisinin-HDACi hybrid molecules. The hybrid molecules showed potent activity against P. falciparum parasites and leukemia cell lines, indicating their potential as antimalarial and antileukemia drug leads.
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 (alpha)-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.
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