Date of Award
1-1-2022
Document Type
Dissertation
Degree Name
Ph.D. in Pharmaceutical Sciences
First Advisor
Hoang V. Le
Second Advisor
John M. Rimoldi
Third Advisor
Jason J. Paris
School
University of Mississippi
Relational Format
dissertation/thesis
Abstract
Natural products and product-derivatized molecules are significant sources for drug discovery and development, and many have been discovered and developed to treat various diseases, including cancer, infectious diseases, neurological disorders, etc. This dissertation reports on the progress of our natural product-inspired research in the discovery of new compounds to treat cancer, infectious diseases, and neuroHIV.
We discovered many glutamine-based compounds and prodrugs that are effective in suppressing the growth of several breast cancer cell lines without introducing cytotoxicity in a non-cancerous cell line. Our lead compound has shown good exposure to the brain, and several compounds were also found to effectively suppress the growth of glioblastoma and head and neck cancer cell lines. These results suggest broad applications of the compounds in anticancer therapy.
Additionally, our structure-based drug design approach has produced several 2-hydroxy-1,4-naphthoquinone analogues that demonstrated great activity against chloroquine-sensitive, chloroquine-resistant, multidrug-resistant, and atovaquone-resistant malarial strains of P. falciparum in vitro. We also discovered a new 2-hydroxy-1,4-naphthoquinone-based lead against methicillin-resistant staphylococcus aureus. We studied the structure-activity relationship of this lead molecule and increased the activity, which was similar to the control ciprofloxacin.
Furthermore, we developed a neurosteroid analogue, 5α-pregnan-2β,3α-diol-20-one, that displayed protective activity against HIV neurotoxicity using a ligand-based drug design approach coupled with computational modeling. Further structure-based design is being carried out to develop more potent analogues to treat neuroHIV.
We also used a structure-based drug design approach on the crystal structure of active-state kappa opioid receptor (KOR) and produced a salvinorin analogue, which we named salvimadol, that showed high agonism and selectivity toward KOR over other opioid receptors such as mu (MOR) and delta (DOR), similar to those of salvinorin A.
This dissertation also reports our improved methods for the synthesis of isoxazole in water and α-C–H functionalization of tertiary amides.
In conclusion, progress has been made in natural product-inspired drug discovery. While there are still many challenges to the progress of the field, including technical barriers in isolation, characterization, and optimization, future aspects of natural products in drug discovery remain bright with continuously improved analytical tools, genetic engineering strategies, and advanced microbial cultures.
Recommended Citation
Khan, Md Imdadul Huque, "Progress in Natural Product-Inspired Drug Discovery" (2022). Electronic Theses and Dissertations. 2440.
https://egrove.olemiss.edu/etd/2440
Concentration/Emphasis
Chemistry