title: Design of substituted bis-Tetrahydrofuran (bis-THF)-derived Potent HIV-1 Protease Inhibitors, Protein-ligand X-ray Structure, and Convenient Syntheses of bis-THF and Substituted bis-THF Ligands.
abstract: We investigated substituted bis-THF-derived HIV-1 protease inhibitors in order to enhance ligand-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; IC(50) = 2.4 nM) among the inhibitors. An X-ray structure of 23c-bound HIV-1 protease 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.
authors.affiliation: Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Cuthbert D
authors.initials: CD
authors.lastname: Martyr
authors.forename: Melinda
authors.initials: M
authors.lastname: Steffey
authors.forename: Yuan-Fang
authors.initials: YF
authors.lastname: Wang
authors.forename: Johnson
authors.initials: J
authors.lastname: Agniswamy
authors.forename: Masayuki
authors.initials: M
authors.lastname: Amano
authors.forename: Irene T
authors.initials: IT
authors.lastname: Weber
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya