Synthesis of Tipranavir Analogues as Non-Peptidic HIV Protease Inhibitors

An analogue of Tipranavir was designed by replacing the dihydropyrone core with a 1,3-cyclohexanedione ring. The thio-alkyl group was used as a temporary protection group for α, β-unsaturated cyclohexane-1,3-diketone derivative, and the resulting compound was reacted with an ethyl-organometallic reagent to form the desired Michael addition product. By using this strategy, a more stable analogue of Tipranavir was synthesized and exhibited excellent HIV protease inhibition (12 nM Ki).