The work done in this project has been an integral part of a team effort with NCI and NIAID laboratories to develop new inhibitors of HIV that target the highly conserved nucleocapsid protein (NCp7). The Bioorganic Chemistry Section has had the responsibility to design the actual drug candidates and to carry out their synthesis and characterization. This past year we have carried out a vigorous program of synthesis of N-substituted 2-mercaptobenzamide thioesters in order to improve the oral bioavailability profile as predicted for drug-like molecules. In addition, we had explored a variety of chemotypes based on replacing the thioester bond with other potentially reactive acylating functions, most notably, thiolcarbamate and thiolcarbonate moieties. These latter derivatives proved too unstable in serum for yielding a satisfactory pharmacokinetic profile. Our re-emphasis on thioesters allowed us to design and successfully test compounds with far greater stability toward serum enzyme-promoted hydrolysis. Many of these compounds are active against HIV-1, HIV-2 and SIV, indicating a highly conserved target. Extensive in vitro and in vivo assays and tests have been performed including ones showing oral bioavailaility and antiviral activity against chronically and latently infected cells and infected PBMCs. A carefully updated patent application (PCT) was filed on July 24, 2002 covering the acyl thiols and active free thiols.
