In vitro activity: BMS-538203 is a novel and highly efficient HIV integrase inhibitor and antiviral agent. BMS-538203 was discovered by a hit-to-clinical candidate pathway that resulted in 50- and 2000-fold improvements in enzyme-inhibition and antiviral activity without an increase in molecular weight or change in molecular topology. The original hit, 1 (mw = 268) was optimized in a stepwise manner. Potential covalent protein-binding moieties were removed by reducing the number of the ketone groups. High enzyme inhibition activity was achieved by optimizing the aryl-portion of the molecule. Protein binding was reduced by replacing the standard amide by the corresponding methyl-hydroxamide. This eventually led to the discovery of compound 2 (BMS-538203, mw = 269) a highly efficient inhibitor and antiviral agent.