RESUMO
A novel class of phosphonate derivatives was designed to mimic the interaction of product-like carboxylate based inhibitors of HCV NS3 protease. A phosphonic acid (compound 2) was demonstrated to be a potent HCV NS3 protease inhibitor, and a potential candidate for treating HCV infection. The syntheses and preliminary biological evaluation of this phosphonate class of inhibitor are described.
Assuntos
Antivirais/síntese química , Hepacivirus/efeitos dos fármacos , Organofosfonatos/síntese química , Inibidores de Serina Proteinase/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/química , Antivirais/farmacocinética , Linhagem Celular Tumoral , Simulação por Computador , Cães , Descoberta de Drogas , Humanos , Organofosfonatos/química , Organofosfonatos/farmacocinética , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacocinética , Proteínas não Estruturais Virais/metabolismoRESUMO
The construction of 1-azaspirocyclic cycloalkanones using a siloxy-epoxide semipinacol ring expansion process was examined. Functionalized 1-azaspiro[5.5]undecan-7-ones (1-azaspirocyclic cyclohexanones) proceeded in high chemical yields with complete diastereoselectivity using titanium tetrachloride as the Lewis acid promoter. The formation of functionalized 6-azaspiro[5.4]-decan-1-ones (1-azaspirocyclic cyclopentanones) proceeded in high chemical yield with little diastereoselectivity. Modification of reaction parameters such as the Lewis acid promoter or the nature of the silyl ether allowed for the preferential formation of either ("anti" or "syn" 1,2 alkyl shift) diastereomeric product. An explanation for the different reactivity profiles between the cyclobutanol silyl ethers and cyclopentanol silyl ethers is provided.
