期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 39, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2021.127884
关键词
Antimalarial drug; Plasmodium falciparum; Artemisinin resistance; Quiescence; Drug combination; Hybrid molecule
资金
- French Agence Nationale de la Recherche (ANR) [INMAR ANR16 CE35 0003]
- Centre National de la Recherche Scientifique
- Sanofi-Institut Pasteur award
Relying on the identification of relevant malaria targets in the context of artemisinin resistance, novel drug combinations and hybrids demonstrated remarkable antimalarial activity against both artemisinin-sensitive and artemisinin-resistant Plasmodium falciparum parasites, highlighting their therapeutic potential.
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 artemisininresistant 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.
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