Design, Synthesis, and X-ray Structure of Substituted Bis-tetrahydrofuran (Bis-THF)-Derived Potent HIV-1 Protease Inhibitors

作者：Ghosh Arun K^*; Martyr Cuthbert D; Steffey Melinda; Wang Yuan Fang; Agniswamy Johnson; Amano Masayuki; Weber Irene T; Mitsuya Hiroaki

来源：ACS Medicinal Chemistry Letters, 2011, 2(4): 298-302.

DOI：10.1021/ml100289m

• HIV-1 protease inhibitors
• Darunavir
• bis-THF
• drug-resistant
• design
• synthesis
• X-ray structure

We investigated substituted bis-THF-derived HIV-1 protease inhibitors in order to enhance liga:nd-binding site interactions in the HIV-1 protease active site. In this context:, we have carried out convenient syntheses of optically active bis-THF and C4-substituted bis-THF ligands using a [2,3]-sigmatropic rearrangement as the key step. The synthesis provided convenient access to a number of substituted bis-THF derivatives. Incorporation of these ligands led to a series of potent HIV-1 protease inhibitors. Inhibitor 23c turned out to be the most potent (K-i = 2.9 pM; IC50 = 2.4 nM) among the inhibitors. An X-ray structure of 23c-bound HIV-1 protease e showed extensive interactions of the inhibitor with the protease active site, including a unique water-mediated hydrogen bond to the Gly-48 amide NH in the S2 site.

• 出版日期2011-4