2. Academic Validation
  3. Novel molecule combinations and corresponding hybrids targeting artemisinin-resistant Plasmodium falciparum parasites

Novel molecule combinations and corresponding hybrids targeting artemisinin-resistant Plasmodium falciparum parasites

  • Bioorg Med Chem Lett. 2021 May 1:39:127884. doi: 10.1016/j.bmcl.2021.127884.
Manel Ouji 1,  Michel Nguyen 1,  Romain Mustière 2,  Tony Jimenez 2,  Jean-Michel Augereau 1,  Françoise Benoit-Vical 3,  Céline Deraeve 4
Affiliations

Affiliations

  • 1 LCC-CNRS, Laboratoire de Chimie de Coordination, Université de Toulouse, CNRS, UPS, Toulouse, France; Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, France; New Antimalarial Molecules and Pharmacological Approaches, ERL Inserm UMR 1289, Toulouse, France.
  • 2 LCC-CNRS, Laboratoire de Chimie de Coordination, Université de Toulouse, CNRS, UPS, Toulouse, France.
  • 3 LCC-CNRS, Laboratoire de Chimie de Coordination, Université de Toulouse, CNRS, UPS, Toulouse, France; Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, France; New Antimalarial Molecules and Pharmacological Approaches, ERL Inserm UMR 1289, Toulouse, France. Electronic address: francoise.vical@inserm.fr.
  • 4 LCC-CNRS, Laboratoire de Chimie de Coordination, Université de Toulouse, CNRS, UPS, Toulouse, France. Electronic address: celine.deraeve@lcc-toulouse.fr.
PMID: 33636304 DOI: 10.1016/j.bmcl.2021.127884
Abstract

Malaria is still considered as the major parasitic disease and the development of artemisinin resistance does not improve this alarming situation. Based on the recent identification of relevant malaria targets in the artemisinin resistance context, novel drug combinations were evaluated against artemisinin-sensitive and artemisinin-resistant Plasmodium falciparum parasites. Corresponding hybrid molecules were also synthesized and evaluated for comparison with combinations and individual pharmacophores (e.g. atovaquone, mefloquine or triclosan). Combinations and hybrids showed remarkable antimalarial activity (IC50 = 0.6 to 1.1 nM for the best compounds), strong selectivity, and didn't present any cross-resistance with artemisinin. Moreover, the combination triclosan + atovaquone showed high activity against artemisinin-resistant parasites at the quiescent stage but the corresponding hybrid lost this pharmacological property. This result is essential since only few molecules active against quiescent artemisinin-resistant parasites are reported. Our promising results highlight the potential of these combinations and paves the way for pharmacomodulation work on the best hybrids.

Keywords

Antimalarial drug; Artemisinin resistance; Drug combination; Hybrid molecule; Plasmodium falciparum; Quiescence.

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