Design and Synthesis of New Potent C sub(2)-Symmetric HIV-1 Protease Inhibitors. Use of L-Mannaric Acid as a Peptidomimetic Scaffold

A study on the use of derivatized carbohydrates as C sub(2)-symmetric HIV-1 protease inhibitors has been undertaken. L-Mannaric acid (6) was bis-O-benzylated at C-2 and C-5 and subsequently coupled with amino acids and amines to give C sub(2)-symmetric products based on C-terminal duplication. Potent HIV protease inhibitors, 28 K sub(i) = 0.4 nM and 43 K sub(i) = 0.2 nM, have been discovered, and two synthetic methodologies have been developed, one whereby these inhibitors can be prepared in just three chemical steps from commercially available materials. A remarkable increase in potency going from IC sub(50) = 5000 nM (23) to IC sub(50) = 15 nM (28) was observed upon exchanging -COOMe for -CONHMe in the inhibitor, resulting in the net addition of one hydrogen bond interaction between each of the two -NH- groups and the HIV protease backbone (Gly 48/148). The X-ray crystal structures of 43 and of 48 have been determined, revealing the binding mode of these inhibitors which will aid further design.