Probing Mercaptobenzamides as HIV Inactivators via Nucleocapsid Protein 7

Human immunodeficiency virus type 1 (HIV‐1) nucleocapsid protein 7 (NCp7), a zinc finger protein, plays critical roles in viral replication and maturation and is an attractive target for drug development. However, the development of drug‐like molecules that inhibit NCp7 has been a significant challenge. In this study, a series of novel 2‐mercaptobenzamide prodrugs were investigated for anti‐HIV activity in the context of NCp7 inactivation. The molecules were synthesized from the corresponding thiosalicylic acids, and they are all crystalline solids and stable at room temperature. Derivatives with a range of amide side chains and aromatic substituents were synthesized and screened for anti‐HIV activity. Wide ranges of antiviral activity were observed, with IC 50 values ranging from 1 to 100 μ m depending on subtle changes to the substituents on the aromatic ring and side chain. Results from these structure–activity relationships were fit to a probable mode of intracellular activation and interaction with NCp7 to explain variations in antiviral activity. Our strategy to make a series of mercaptobenzamide prodrugs represents a general new direction to make libraries that can be screened for anti‐HIV activity.