Graduation Term

2023

Degree Name

Master of Science (MS)

Department

Department of Chemistry

Committee Chair

Shawn R. Hitchcock

Abstract

The Centers for disease control and Prevention (CDC) published an article describing the disease that would later become known as HIV/AIDS in 1981. There were no treatments for this new disease, and by the time patients began exhibiting detectable symptoms, it would be too late to provide any meaningful treatments. Through the efforts made by the scientific community and social activism, new classes of drugs appeared for the treatment of this disease. These drugs are highly effective when combined with other therapeutic agents that suppress the proliferation of the virus. These combined therapies have helped alleviate the previously insurmountable risks of HIV from a fatal viral infection to a manageable chronic disease. In this regard, one class of HIV drug that has proven to be highly effective is that of the HIV protease inhibitors (PI). However, despite the success of these PI drug agents, there is the continuous emergence of drug-resistant strains of the HIV virus. In this context, there is an ongoing effort to synthesize novel PIs with higher specificity, selectivity, and greater efficacy against HIV infection. Ghosh and co-workers synthesized and reported the first ever HIV PI, Amprenavir, in 1998. The structure was designed based on the various available 3D structures of the protein-ligand complexes of the HIV protease binding site. Through further computational studies and structural activity relationship (SAR) studies, the next-generation drug, Darunavir was synthesized, and it currently exhibits a higher efficacy relative to Amprenavir. Most of the efforts in the recent development of HIV PI drugs involve the structural activity relationship (SAR) studies of Darunavir. The current methods that are being employed, however, are intrinsically limited in terms of the development of potential derivatives. To these effects, the Hitchcock has group has developed a new synthetic pathway the utilizes an asymmetric glycolate aldol addition reaction to circumvent the limitations and offer shorter but robust synthetic pathways for SAR studies of derivatives of Darunavir. To prove the effectiveness of our new synthetic pathway, three derivatives (35a, 35b, and 35c) of darunavir have been synthesized using our newly designed synthetic pathway.

Access Type

Thesis-Open Access

DOI

https://doi.org/10.30707/ETD2023.20231004061827367487.999997

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