Procainamide–SAHA Fused Inhibitors of hHDAC6 Tackle Multidrug-Resistant Malaria Parasites
Flore Nardella, Ludovic Halby, Irina Dobrescu, Johanna Viluma, Corentin Bon, Aurélie Claës, Véronique Cadet-Daniel, Ambre Tafit, Camille Roesch, Elie Hammam, Diane Erdmann, Mélissa Mairet-Khedim, Roger Péronet, Salaheddine Mécheri, Benoît Witkowski, Artur Scherf, Paola B. Arimondo
Abstract
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.