Design, synthesis, and biological evaluation of new 1,2,3-triazolo-2'-deoxy-2'-fluoro- 4'-azido nucleoside derivatives as potent anti-HBV agents.
Eur J Med Chem
; 143: 137-149, 2018 Jan 01.
Article
em En
| MEDLINE
| ID: mdl-29174810
ABSTRACT
Novel drugs are urgently needed to combat hepatitis B virus (HBV) infection due to drug-resistant virus. In this paper, a series of novel 4-monosubstituted 2'-deoxy-2'-ß-fluoro-4'-azido-ß-d-arabinofuranosyl 1,2,3-triazole nucleoside analogues (1a-g) were designed, synthesized and screened for in vitro anti-HBV activity. At 5.0 µM in the cellular model, all the synthetic compounds display activities comparable to that of the positive control, lamivudine at 20 µM. Of the compounds tested, the amide-substituted analogue (1a) shows the most promising anti-HBV activity and low cytotoxicity in the cell model. In particular, it retains excellent activity against lamivudine-resistant HBV mutants. In duck HBV (DHBV)-infected duck models, both the serum and liver DHBV DNA levels (67.4% and 53.3%, respectively) were reduced markedly by the treatment with 1a. Analysis of the structure of HBV polymer/1a-triphosphate (1a-TP) complex shows that 1a-TP is stabilized by specific van der Waals interactions with the enzyme residues arising from 4-amino-1,2,3-triazole and the 4'-azido group.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
2_ODS3
Base de dados:
MEDLINE
Assunto principal:
Antivirais
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Triazóis
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Desenho de Fármacos
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Vírus da Hepatite B do Pato
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Vírus da Hepatite B
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Hepatite B
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Monossacarídeos
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Nucleosídeos
Limite:
Animals
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Humans
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2018
Tipo de documento:
Article