Procainamide–SAHA Fused Inhibitors of hHDAC6 Tackle Multidrug-Resistant Malaria Parasites

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 DNA methyltransferase procainamide. A three- or four-step chemical synthesis was designed starting from cheap raw materials. Compared to single drugs, combined molecules showed a superior activity in Plasmodium potent inhibition against HDAC6, exerting no cytotoxicity cell lines. These compounds fully active multidrug-resistant falciparum Cambodian isolates. They target transmission of by inducing irreversible morphological changes gametocytes inhibiting exflagellation. The slow-acting have an additive antimalarial effect combination fast-acting epidrugs dihydroartemisinin. lead compound decreases parasitemia mice severe model. Taken together, this novel fused molecule offers affordable alternative current failing therapy.