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.

In this work, we synthesized a series of peptoid-based HDAC inhibitors with variations in the linker region and zinc-binding groups. All compounds were investigated for their HDAC inhibition, antiplasmodial activity, and cytotoxicity against native and cisplatin-resistant carcinoma cell lines. The ethylhydrazide 20 (DS-103) proved to be the most effective compound in these primary screenings. DS-103 showed nanomolar inhibition of class I HDACs and of HDAC6 (class IIb). To further investigate the binding mode of DS-103, a crystal structure of DS-103 in complex with HDAC6 was obtained, which represents the first reported crystal structure of an alkylhydrazide in complex with an HDAC enzyme. Importantly, DS-103 completely reversed cisplatin resistance in two different platinum-resistant solid cancer cell lines and demonstrated strong synergism with cisplatin. The synergistic anticancer effects are mediated by increased DNA damage and p21 expression, resulting in caspase-mediated apoptosis and cell death.

Epigenetic drug targets have become an important focus in drug discovery. One of the key mechanisms in epigenetics is the acetylation and deacetylation of histone proteins. In this study, we synthesized and evaluated novel histone deacetylase (HDAC) inhibitors derived from the clinical candidate quisinostat. A library of 16 compounds categorized in three novel chemotypes was rapidly generated using multicomponent reactions (MCRs), enabling efficient structure-activity relationship studies. The compounds were evaluated for their activity against Plasmodium falciparum, the main malaria parasite, and solid cancer cell lines. The antiplasmodial activity was assessed against P. falciparum strains 3D7 and Dd2, identifying compound 18b of the type C series as the most potent. It demonstrated low nanomolar IC50 values (IC50 (3D7) = 0.023 µM; IC50 (Dd2) = 0.047 µM) and high parasite selectivity (SIMRC-5/Pf3D7 > 2174). Docking studies suggested distinct binding modes of 18b with P. falciparum and human HDAC1. The in vitro anticancer activity was also evaluated in the Cal27 and HepG2 cell lines and compounds 9b, 9d, and 13f showed potent antiproliferative activity. Compound 9d significantly induced caspase 3/7-mediated apoptosis and caused hyperacetylation of histone H3 and α-tubulin, indicating robust cellular target engagement. Overall, in this work we have identified several promising HDAC inhibitors with antimalarial and anticancer activities, providing valuable leads for further drug development efforts aimed at creating derivatives with reduced cytotoxicity compared to quisinostat.

Histone deacetylases (HDACs) are promising targets for epigenetic drug discovery. Additionally, targeted degradation of HDACs has emerged as a novel approach in medicinal chemistry and chemical biology. However, most inhibitors and degraders rely on the potentially genotoxic hydroxamate as a zinc-binding group (ZBG). In this study, we present the development of HDAC6-directed proteolysis-targeting chimeras (PROTACs) featuring an ethyl hydrazide moiety as an alternative ZBG. This approach avoids the genotoxicity concerns of hydroxamates while maintaining potent HDAC6 degradation. We synthesized a series of CRBN- and VHL-recruiting PROTACs and identified several potent HDAC6 degraders (HDAC6 Dmax > 80%). Among these, 17c was the most effective, achieving an HDAC6 degradation of 91% and a DC50 value of 14 nM. Further characterization proved that 17c acts via the ubiquitin-proteasome system and chemoproteomics confirmed selective HDAC6 degradation over other HDAC isoforms.