Procainamide-SAHA fused inhibitors of hHDAC6 tackle multi-drug resistant malaria parasites

Flore Nardella (1) , Ludovic Halby (2) , Irina Dobrescu (1) , Johanna Viluma (2) , Corentin Bon (2) , Aurélie Claes (1) , Véronique Cadet-Daniel (2) , Ambre Tafit (2) , Camille Roesch (3) , Elie Hammam (1) , Diane Erdmann (2) , Melissa Mairet-Khedim (3) , Roger Peronet (1) , Salah Mecheri (1) , Benoit Witkowski (3) , Artur Scherf (1) , Paola B Arimondo (2)

1 Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions
2 EpiCBio - Chimie biologique épigénétique - Epigenetic Chemical Biology
3 MMEU - Malaria Molecular Epidemiology

Epigenetic post-translational modifications are essential for human malaria parasite survival and progression through its life cycle. Here, we present new functionalized suberoylanilide hydroxamic acid (SAHA) derivatives that chemically combine the pan-histone deacetylase inhibitor SAHA with the DNA methyltransferase inhibitor procainamide. A three- or four-step chemical synthesis was designed starting from cheap raw materials. Compared to the single drugs, the combined molecules showed a superior activity in Plasmodium and a potent inhibition against human HDAC6, exerting no cytotoxicity in human cell lines. These new compounds are fully active in multidrug-resistant Plasmodium falciparum Cambodian isolates. They target transmission of the parasite by inducing irreversible morphological changes in gametocytes and inhibiting exflagellation. The compounds are slow-acting and have an additive antimalarial effect in combination with fast-acting epidrugs and dihydroartemisinin. The lead compound decreases parasitemia in mice in a severe malaria model. Taken together, this novel fused molecule offers an affordable alternative to current failing antimalarial therapy.

Mots clés: Histone deacetylase; DNA methylation; antimalarial; Plasmodium falciparum; parasite; in vivo; malaria; HDAC6 inhibitors; drug resistance

Domaines: Pharmacologie; Parasitologie; Chimie thérapeutique

Flore Nardella, Ludovic Halby, Irina Dobrescu, Johanna Viluma, Corentin Bon, et al.. Procainamide-SAHA fused inhibitors of hHDAC6 tackle multi-drug resistant malaria parasites. Journal of Medicinal Chemistry, 2021, 64 (14), pp.10403-10417. ⟨10.1021/acs.jmedchem.1c00821⟩. ⟨hal-03264653⟩