ß-Hydroxy- and ß-Aminophosphonate Acyclonucleosides as Potent Inhibitors of Plasmodium falciparum Growth.
J Med Chem
; 63(15): 8069-8087, 2020 08 13.
Article
em En
| MEDLINE
| ID: mdl-32687714
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 ß-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 â¼ 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Plasmodium falciparum
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Malária Falciparum
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Antimaláricos
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article