Discovery of novel integrase-LEDGF/p75 allosteric inhibitors based on a benzene scaffold

We report herein the discovery of novel integrase-LEDGF/p75 allosteric inhibitors (INLAIs) based on a benzene scaffold 3. This scaffold can extend substituents from the C1 position unlike the common pyridine scaffolds 2. Structure-activity relationship studies showed that the sulfonamide linker at the C1 position was important for the antiviral activity. Interaction between sulfonamide and Q95 was observed by X-ray crystallography. Compound 31h showed more potent antiviral activity (EC₅₀ (NL432) = 3.9 nM) than BI-224436 (EC₅₀ (NL432) = 56 nM), suggesting the potential of the newly designed scaffold 3.