DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF POTENT HIV-1 PROTEASE INHIBITORS WITH NOVEL BICYCLIC OXAZOLIDINONE AND BIS SQUARAMIDE SCAFFOLDS

2019-08-16T16:41:03Z (GMT) by Jacqueline N Williams

In 2018, the World Health Organization (WHO) reported approximately 37 million people are living with the Human Immunodeficiency Virus (HIV). Suppressing replication of the virus down to undetectable levels was achieved by combination antiretroviral therapy (cART) which effectively reduced the mortality and morbidity rates of HIV positive individuals. Despite the improvements towards combatting HIV/AIDS, no successful treatment exists to eradicate the virus from an infected individual. Treatment regimens are lifelong and prompt less than desirable side effects including but not limited to; drug-drug interactions, toxicity, systemic organ complications, central nervous system HIV triggered disorders and most importantly, drug resistance. Current therapies are becoming ineffective against highly resistant HIV strains making the ability to treat long-term viral suppression a growing issue. Therefore, potent and more effective HIV inhibitors provide the best chance for long-term successful cART.

HIV-1 protease (PR) enzyme plays a critical role in the life cycle and replication of HIV. Significant advancements were achieved through structure-based design and X-ray crystallographic analysis of protease-bound to HIV-1 and brought about several FDA protease inhibitors (PI). Highly mutated HIV-1 variants create a challenge for current and future treatment regimens. This thesis work focuses on the design, synthesis, and evaluation of two new classes of potent HIV-1 PIs that exhibit a novel bicyclic oxazolidinone feature as the P2 ligand and a novel bis squaramide scaffold as the P2/P3 ligand. Several inhibitors displayed good to excellent activity toward HIV-1 protease and significant antiviral activity in MT-4 cells. Inhibitors 1.65g and 1.65h were further evaluated against a panel of highly resistant multidrug-resistant HIV-1 variants and displayed antiviral activity similar to Darunavir. X-ray crystal structures of inhibitor 1.65a and inhibitor 1.65i were co-crystallized with wild type HIV-1 protease and solved at a 1.22 Å and 1.30 Å resolution and maintained strong hydrogen bond with the backbone of the PR enzyme.