Facile syntheses of C2-symmetrical HIV-1 protease inhibitors.

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 alpha,alpha'-dibromoketones 4a-d, we synthesised the diamino compounds 6a-c by Gabriel synthesis, which were then coupled with Z-valine to yield inhibitors including a central hydroxy group 8a-d a-i by azidation, reduction with LiAlH4 and coupling of the beta,beta'-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 microM.