The copper (I)-mediated cycloaddition of organic azides and a terminal alkynes (CuAAC) to give a 1,4-triazole is one of a number of “click” reactions that we are applying in the quest to rapidly identify new and potent HIV protease inhibitors.  The CuAAC reaction is well suited for this task because the cycloaddition is clean, goes to completion quickly and has benign side products.  This allows us to screen the crude reaction mixtures directly without purifying the individual compounds.

Herein we present our work where we combined diverse sets of azides 1 and alkynes 2 to give a library of triazoles 3.  After screening the crude reaction mixtures, a subset of triazoles 4 were identified that gave 29 to 87% inhibition of HIV-1 protease.  Further optimization of R¹ and R² and functionalization of the triazole with R³, produced inhibitors 5, with K_i values as low as 8 nM.