Pharmacophore-based design of novel 3-hydroxypyrimidine-2,4-dione subtypes as inhibitors of HIV reverse transcriptase-associated RNase H: Tolerance of a nonflexible linker.
Eur J Med Chem
; 166: 390-399, 2019 Mar 15.
Article
em En
| MEDLINE
| ID: mdl-30739822
ABSTRACT
The pharmacophore of active site inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated RNase H typically entails a flexible linker connecting the chelating core and the hydrophobic aromatics. We report herein that novel 3-hydroxypyrimidine-2,4-dione (HPD) subtypes with a nonflexible C-6 carbonyl linkage exhibited potent and selective biochemical inhibitory profiles with strong RNase H inhibition at low nM, weak to moderate integrase strand transfer (INST) inhibition at low µM, and no to marginal RT polymerase (pol) inhibition up to 10⯵M. A few analogues also demonstrated significant antiviral activity without cytotoxicity. The overall inhibitory profile is comparable to or better than that of previous HPD subtypes with a flexible C-6 linker, suggesting that the nonflexible carbonyl linker can be tolerated in the design of novel HIV RNase H active site inhibitors.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirimidinonas
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HIV-1
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Inibidores Enzimáticos
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Ribonuclease H do Vírus da Imunodeficiência Humana
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Transcriptase Reversa do HIV
Tipo de estudo:
Risk_factors_studies
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article