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
  • 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.