Sulfanylbenzamides with Unique Side Chains to Improve Metabolic Stability, Pharmacokinetics, and Anti-HIV Activity

Molecules that inhibit HIV by mechanisms other than inhibition of viral enzymes may be helpful in the treatment of infections where viral resistance has developed. Simple sulfanylbenzamides inactivate HIV by disrupting the coordination of zinc in the viral nucleocapsid protein, resulting in immature and noninfectious virus. HIV nucleocapsid protein (NCp7) is highly conserved across all viral strains, and there is a very high barrier for the virus to develop resistance to sulfanylbenzamide inactivators. These types of molecules act as topical microbicides to prevent HIV infections in animal models, but their systemic use has not been possible due to rapid metabolism in the blood. In this article, we describe a strategy to chemically modify the side chains of sulfanylbenzamides with unique groups to protect the molecules from metabolism while preserving antiviral activity and low toxicity. In vivo pharmacokinetics demonstrates the success of this approach, leading to a new route of systemic administration for this class of molecules.