Bicyclic Hydroxy-1H-pyrrolopyridine-trione Containing HIV-1 Integrase Inhibitors

摘要

HIV-1 integrase (IN) is a validated therapeutic target for the treatment of AIDS. However, the emergence of resistance to Raltegravir, the sole marketed FDA-approved IN inhibitor, emphasizes the need to develop second-generation inhibitors that retain efficacy against clinically-relevant IN mutants. We report herein bicyclic hydroxy-1H-pyrrolopyridine-triones as a new family of HIV-1 integrase inhibitors that were efficiently prepared using a key “Pummerer cyclization deprotonation cycloaddition” cascade of imidosulfoxides. In in vitro HIV-1 integrase assays the analogues showed low micromolar inhibitory potencies with selectively for strand transfer reactions as compared with 3’-processing inhibition. A representative inhibitor (>5e) retained most of its inhibitory potency against the three major raltegravir-resistance mutant IN enzymes, G140S/Q148H, Y143R and N155H. In antiviral assays employing viral vectors coding these IN mutants, compound >5e was approximately 200-fold and 20-fold less affected than raltegravir against the G140S/Q148H and Y143R mutations, respectively. Against the N155H mutation >5e was approximately 10-fold less affected than raltegravir. Thus, our new compounds represent a novel structural class that may be further developed to overcome resistance to raltegravir, particularly in the case of the G140S/Q148H mutations.