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On the inhibition of HIV-1 protease by hydrazino-ureas displaying the N-->C=O interaction.
Waibel, Michael; Pitrat, Delphine; Hasserodt, Jens.
Afiliação
  • Waibel M; Laboratoire de Chimie, UMR CNRS 5182, Université de Lyon-ENS, 46 allée d'Italie, 69364 Lyon cedex 07, France.
Bioorg Med Chem ; 17(10): 3671-9, 2009 May 15.
Article em En | MEDLINE | ID: mdl-19394228
To create novel HIV-1 protease (HIV PR) inhibitors, we have extended our investigations of the N-->C=O interaction as a moiety that reproduces electrostatic properties of the transition state of peptidolysis. Consequently, we prepared a series of compounds with an unusual hydrazino-urea core. In polar protic media, these adopt solely a cyclic constitution displaying the interaction on one side of the molecule while offering a urea moiety on the opposite side meant to hydrogen-bond with the enzyme flaps. Each inhibitor candidate was obtained via a key series of three synthetic steps employing carbonyl-di-imidazole (CDI). It was thus possible to efficiently fuse two independent building blocks, a hydrazine and a protected aminoaldehyde in a convergent manner. NMR and UV analysis proved that all compounds, when dissolved in polar protic media, existed exclusively in the cyclic constitution exhibiting the N-->C=O interaction. In total, five inhibitor candidates were tested with HIV PR for their potency. The one carrying the least bulk in peripheral substituents showed the highest activity. Its very low molecular weight (365 g/mol) holds great promise for future improvements in affinity without violating Lipinski's rule of remaining within the limit of 500 g/mol.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ureia / Inibidores da Protease de HIV / Hidrazinas Limite: Humans Idioma: En Revista: Bioorg Med Chem Ano de publicação: 2009 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ureia / Inibidores da Protease de HIV / Hidrazinas Limite: Humans Idioma: En Revista: Bioorg Med Chem Ano de publicação: 2009 Tipo de documento: Article