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

• Main Authors: Lukas von Bredow (Author), Thomas Martin Schäfer (Author), Julian Hogenkamp (Author), Maik Tretbar (Author), Daniel Stopper (Author), Fabian B. Kraft (Author), Julian Schliehe-Diecks (Author), Andrea Schöler (Author), Arndt Borkhardt (Author), Sanil Bhatia (Author), Jana Held (Author), Finn K. Hansen (Author)
• Format: Book
• Published: MDPI AG, 2022-03-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/ph15030333; 1424-8247
• Keywords: histone deacetylase; artemisinin; multitarget drugs; Medicine; R; Pharmacy and materia medica; RS1-441
• Source: Pharmaceuticals, Vol 15, Iss 3, p 333 (2022)

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 <i>P. falciparum</i> 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 <i>P. falciparum</i> with IC₅₀ values in the single-digit nanomolar range. Furthermore, the hybrid (α)-<b>7c</b> 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 (<b>7a-e</b>) and the <i>ortho</i>-aminoanilide <b>8</b> 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.