Design and synthesis of highly potent HIV-1 protease inhibitors and the development of synthetic methods for benzofused oxabicyclooctanes and nonanes
Substituted bis-THF containing protease inhibitors were designed to optimize ligand-enzyme interaction within the active site of the HIV protease. The [2,3]-sigmatropic rearrangement was used to gain access to the bis-THF ligand and C3-substituted bis-THF ligands. Incorporation of these ligands into the hydroxyethylamine isostere led to a series of highly potent HIV-1 protease inhibitors. Inhibitor 59f and 59g were the most potent among the O-substituted inhibitors. An X-ray structure of 59f -bound HIV-1 protease showed extensive interactions of the inhibitor with the protease active site, including a unique water-mediated hydrogen bond to the Gly48 amide NH in the S2-subsite. Evaluation of C4-amine bis-THF containing protease inhibitor 75c revealed the presence of a direct hydrogen bond interaction with the C3-NH and the carbonyl of Gly48. The [2,3]-sigmatropic rearrangement has been applied to the synthesis of tetrahydropyran-tetrahydrofuran (Tp-THF) and C3-substituted Tp-THF ligands. Tp-THF containing protease inhibitors were designed to optimize ligand-enzyme interaction within the enzyme active site of the HIV protease. Incorporation of these ligands led to a series of highly potent HIV-1 protease inhibitors. Presumably, the increased activity observed for these inhibitors results from an increased network of hydrogen bonds within the S 2-subsite of the enzyme active site. Inhibitor 105b, 105h displayed the most significant result when evaluated in enzymatic and cellular assays. C3 amine containing protease inhibitors 105n and 105o 105n had a Ki = 0.9 pM and 105o had a Ki=1.3 nM. Continuing our studies in probing the enzyme active site a convenient synthesis of substituted benzo-fused 8-oxabicyclo[3.2.1]octane and 9-oxabicyclo[4.2.1]nonane derivatives were developed. The reaction involved a TiCl 4-mediated tandem carbonyl or imine addition followed by an intramolecular Friedel-Crafts cyclization to give these functionalized derivatives in good to excellent yields and high diastereoselectivity. The X-ray crystal structure of 144b provided valuable information about the relative stereochemistry of these compounds.
Ghosh, Purdue University.
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