| Cysteine proteases are important pharmaceutical targets because of their role in biological functions and diseases. Described in this dissertation is a solid-supported method to access ketone-containing mechanism-based cysteine protease inhibitors. This method represents the first general strategy that allows for full display of functionality at all variable sites about the ketone scaffold without racemization of the α-stereocenter. Libraries of amidomethyl and mercaptomethyl ketones were prepared using this synthesis method and then screened against the cysteine protease cruzain, resulting in the rapid identification of inhibitors with low nanomolar activity. In addition, a second parallel synthesis strategy towards ketone-containing inhibitors was developed to provide greater P1 side chain diversity. This seven-step solution-phase synthesis sequence combines the use of liquid-liquid extraction, volatile reagents, and support-bound scavengers and reagents in order to avoid intermediate column chromatographic purification. |
