β-Hydroxy- and β-Aminophosphonate Acyclonucleosides as Potent Inhibitors of Plasmodium falciparum Growth

Journal of Medicinal Chemistry
Thomas ChevietSuzanne Peyrottes

Abstract

Malaria is an infectious disease caused by a parasite of the genus Plasmodium, and the emergence of parasites resistant to all current antimalarial drugs highlights the urgency of having new classes of molecules. We developed an effective method for the synthesis of a series of β-modified acyclonucleoside phosphonate (ANP) derivatives, using commercially available and inexpensive materials (i.e., aspartic acid and purine heterocycles). Their biological evaluation in cell culture experiments and SAR revealed that the compounds' effectiveness depends on the presence of a hydroxyl group, the chain length (four carbons), and the nature of the nucleobase (guanine). The most active derivative inhibits the growth of Plasmodium falciparum in vitro in the nanomolar range (IC50 = 74 nM) with high selectivity index (SI > 1350). This compound also showed remarkable in vivo activity in P. berghei-infected mice (ED50 ∼ 0.5 mg/kg) when administered by the ip route and is, although less efficient, still active via the oral route. It is the first ANP derivative with such potent antimalarial activity and therefore has considerable potential for development as a new antimalarial drug.

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Apr 10, 2019·Journal of Medicinal Chemistry·Thomas ChevietSuzanne Peyrottes

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Citations

Feb 11, 2021·Beilstein Journal of Organic Chemistry·Kārlis-Ēriks KriķisMāris Turks
Jan 26, 2021·Frontiers in Chemistry·Elisabetta Groaz, Steven De Jonghe
Oct 30, 2020·The Journal of Organic Chemistry·Zhantao YangJunbiao Chang

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Antimalarial Agents (ASM)

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.

Antimalarial Agents

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.

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