RESUMEN

Employing a scaffold hopping approach, a series of allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) have been synthesized based on an indole scaffold. These compounds incorporate the key elements utilized in quinoline-based ALLINIs for binding to the IN dimer interface at the principal LEDGF/p75 binding pocket. The most potent of these compounds displayed good activity in the LEDGF/p75 dependent integration assay (IC50=4.5µM) and, as predicted based on the geometry of the five- versus six-membered ring, retained activity against the A128T IN mutant that confers resistance to many quinoline-based ALLINIs.

Asunto(s)

Inhibidores de Integrasa VIH/farmacología , Integrasa de VIH/efectos de los fármacos , Indoles/farmacología , Regulación Alostérica , Cristalografía por Rayos X , Inhibidores de Integrasa VIH/química , Enlace de Hidrógeno , Relación Estructura-Actividad