Asymmetric synthesis of bis-tetrahydrofuran and its conversion to darunavir and design of novel HIV-1 protease inhibitors based upon the 'backbone binding concept'

The proteolytic enzyme of the human immunodeficiency virus (HIV-PR) plays an important role in the HIV replication cycle and the overall progression of AIDS. Consequently, inhibition of its catalytic activity has been a major target for drug development. During the past two decades, several-FDA approved HIV protease inhibitors (PIs) emerged from X-ray crystallographic studies of enzyme-bound HIV PIs and intensive structure-based design. However, a growing emergence of drug-resistant HIV-1 PR mutants is a growing concern, threatening long-term efficacy of most first generation therapies available to patients.;This thesis work features the synthesis of a new generation of high affinity HIV-1 PIs, designed to demonstrate broad spectrum activity against mutant proteases. Based on our group's 'backbone binding concept', we have designed and synthesized a class of novel hydroxyethylamine isostere-based HIV-PIs incorporating stereochemically defined and optically active pyrrolidinones and an oxazolidinones as P1' ligands, to promote new backbone interactions with the HIV-1 active site. This study led us to inhibitors displaying impressive activity at sub nanomolar to picomolar range (Ki/IC 50 values). Antiviral activity of these inhibitors was tested against several drug-resistant HIV-1 variantts, and one of the inhibitors 55 (GRL-02031) was found to be highly active against numerous mutant strains. It displayed exceedingly potent antiviral activity even against MT 4-human T-lymphoid cells infected with HIVIIIB isolates. This thesis work also includes synthetic studies of bis-THF, a high affinity P2-ligand of the FDA-approved inhibitor, Darunavir. The bis-THF ligand is a privileged ligand designed and developed in our laboratory. We have investigated a photochemical conjugate addition and interplay of functional groups leading to optically active synthesis of stereochemically defined bis-tetrahydrofuran. This optically active ligand was then converted to darunavir.