Design and synthesis of novel HIV-1 protease inhibitors

Garth Lyndon Parham, Purdue University


This dissertation describes the development of HIV protease inhibitors and the design and synthesis of novel P2 ligands for HIV protease inhibitors. Chapter 1 of the dissertation is a concise review of the development and designs incorporated into HIV protease inhibitors. A brief historical background of developing inhibitors for HIV protease is described leading up to FDA second generation protease inhibitors. Also an overview of Ghosh's laboratory contribution to developing potent protease inhibitors and combatting drug resistance is described. Chapter 2 of the dissertation describes the exploratory work performed in designing and synthesizing new novel heterocyclic oxazole P2 ligands for HIV-1 protease inhibitors. Within the ligand is postulated to maintain crucial hydrogen bondings with the catalytic site. An SAR study was developed to examine heteroatom substitutions on the oxazole ring and the heterocyclic ring. P2 ligands with varying ring sizes (5 and 6 membered) were also synthesized and enzyme inhibitory potency compared. Chapter 3 of the dissertation describes a study into designing potent bicyclic and tricyclic P2 ligands for HIV-1 protease inhibitors. This study exploits the use of cycloaddition reactions (Mn[OAc]3, Ag2O and Rh2[OAc]4) to yield fused cyclic precursors to the ligands. This chemistry was utilized for its potential of deriving varying substrates for a ring size and heteroatom SAR study.




Ghosh, Purdue University.

Subject Area

Chemistry|Organic chemistry|Virology

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