Hydroxyazole scaffold-based Plasmodium falciparum dihydroorotate dehydrogenase inhibitors: Synthesis, biological evaluation and X-ray structural studies.
Eur J Med Chem
; 163: 266-280, 2019 Feb 01.
Article
em En
| MEDLINE
| ID: mdl-30529545
ABSTRACT
Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) has been clinically validated as a target for antimalarial drug discovery, as a triazolopyrimidine class inhibitor (DSM265) is currently undergoing clinical development. Here, we have identified new hydroxyazole scaffold-based PfDHODH inhibitors belonging to two different chemical series. The first series was designed by a scaffold hopping strategy that exploits the use of hydroxylated azoles. Within this series, the hydroxythiadiazole 3 was identified as the best selective PfDHODH inhibitor (IC50 12.0⯵M). The second series was designed by modulating four different positions of the hydroxypyrazole scaffold. In particular, hydroxypyrazoles 7e and 7f were shown to be active in the low µM range (IC50 2.8 and 5.3⯵M, respectively). All three compounds, 3, 7e and 7f showed clear selectivity over human DHODH (IC50â¯>â¯200⯵M), low cytotoxicity, and retained micromolar activity in P. falciparum-infected erythrocytes. The crystallographic structures of PfDHODH in complex with compounds 3 and 7e proved their binding mode, supplying essential data for future optimization of these scaffolds.
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Texto completo:
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Plasmodium falciparum
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Oxirredutases atuantes sobre Doadores de Grupo CH-CH
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Inibidores Enzimáticos
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Antimaláricos
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article