Facile Syntheses of C2‐Symmetrical HIV‐1 Protease Inhibitors

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Abstract
With the goal of obtaining inexpensive yet potent anti-AIDS drugs, simple inhibitors of HIV-1 protease were synthesised. The C2-symmetrical pseudopeptidic substrate analogues can be prepared as inhibitors for HIV-1 protease starting from symmetrical ketones 3a–d by a facile four-step synthesis. After bromination of 3a–d to α,α′-dibromoketones 4a–d, we synthesised the diamino compounds 6a–c by Gabriel synthesis, which were then coupled with Z-valine to yield inhibitors with a central keto group 2a–c. We also synthesised inhibitors including a central hydroxy group 8a-d a-i by azidation, reduction with LiAlH4 and coupling of the β,β′-diaminohydroxy compounds with appropriate peptides. The first set of compounds showed only weak inhibition whereas the latter reach Ki values of up to 3.0 μM.