Design, synthesis, and biological evaluation of monopyrrolinone-based HIV-1 protease inhibitors possessing augmented P2′ side chains

A series of monopyrrolinone-based HIV-1 protease inhibitors possessing rationally designed P2′ side chains have been synthesized and evaluated for activity against wild-type HIV-1 protease. The most potent inhibitor displays subnanomolar potency in vitro for the wild-type HIV-1 protease. Additionally, the monopyrrolinone inhibitors retain potency in cellular assays against clinically significant mutant forms of the virus. X-ray structures of these inhibitors bound in the wild-type enzyme reveal important insights into the observed biological activity.

Graphical abstractA series of monopyrrolinone-based HIV-1 protease inhibitors were synthesized and evaluated for activity against wild-type and mutant forms of the virus. X-ray cocrystal structures provide insight into their potent activity.Figure optionsDownload full-size imageDownload as PowerPoint slide