2. Academic Validation
  3. Procainamide-SAHA Fused Inhibitors of hHDAC6 Tackle Multidrug-Resistant Malaria Parasites

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

  • J Med Chem. 2021 Jul 22;64(14):10403-10417. doi: 10.1021/acs.jmedchem.1c00821.
Flore Nardella 1,  Ludovic Halby 2,  Irina Dobrescu 1,  Johanna Viluma 2,  Corentin Bon 2 3,  Aurélie Claes 1,  Véronique Cadet-Daniel 2,  Ambre Tafit 2,  Camille Roesch 4,  Elie Hammam 1,  Diane Erdmann 2 3,  Melissa Mairet-Khedim 4,  Roger Peronet 1,  Salah Mecheri 1,  Benoit Witkowski 4,  Artur Scherf 1,  Paola B Arimondo 2
Affiliations

Affiliations

  • 1 Unité Biologie des Interactions Hôte-Parasite, Département de Parasites et Insectes Vecteurs, Institut Pasteur, CNRS ERL 9195, INSERM Unit U1201, 25-28 Rue du Dr Roux, Paris 75015, France.
  • 2 Epigenetic Chemical Biology, Department of Structural Biology and Chemistry, Institut Pasteur, UMR n°3523, CNRS, 28 Rue du Dr Roux, Paris 75015, France.
  • 3 Ecole Doctorale MTCI ED563, Université de Paris, Sorbonne Paris Cité, Paris 75270, France.
  • 4 Malaria Molecular Epidemiology Unit, Pasteur Institute in Cambodia, Phnom Penh 12201, Cambodia.
PMID: 34185525 DOI: 10.1021/acs.jmedchem.1c00821
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.

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