Date of Award
1-1-2022
Document Type
Dissertation
Degree Name
Ph.D. in Pharmaceutical Sciences
Department
Pharmaceutics and Drug Delivery
First Advisor
Dr. Ikhlas Ikhlas Khan
Second Advisor
Dr. Samir Ross
Third Advisor
Dr. Le Hoang
Relational Format
dissertation/thesis
Abstract
Owing to their complexity, diverse structures and molecular targets, natural products have contributed, and will continue to contribute, to the development and discovery of new drugs. Although natural products provide numerous active compounds, their complex structures and poor pharmacokinetics make meeting the eligibility criteria for clinical trials unfeasible. In order to improve their drug-likeness, structural modification is an effective tool to generate countless natural product-based molecules with potential therapeutics. This proposal entails synthetic efforts towards late-stage diversification of natural products in two projects.
The first study highlights the multi-factorial nature of Alzheimer’s disease and brings attention to the importance of the paradigm shift in drug development for Alzheimer’s from single-targeted ligands to multi-target directed ligands. Clinical trials have shown that drugs targeting proteins such as amyloid-ß and tau failed to slow down or even reverse the progression of Alzheimer’s disease. Consequently, we propose the synthesis of small molecules that are hybrids of lipoic and arundic acids. Lipoic acid is a naturally occurring compound that possesses antioxidant, anti-inflammatory, and reactive oxygen species scavenging properties, however, results from studies on its efficacy and potency against Alzheimer’s remain inconsistent. Arundic acid, on the other hand, has completed phase II clinical trials for the treatment of multiple neurodegenerative diseases including Alzheimer’s, and has displayed in vitro and in vivo neuroprotective potential. Therefore, by combining the structural features of both lipoic acid and arundic acid, multi-functional and bivalent ligands were designed. This approach would potentially synergize the anti-oxidative effects of lipoic acid and the neuroprotective traits of arundic acid.
The second study focuses on the search for a new insecticide to control bed bug infestations. With the emergence of insecticide-resistance acquired by bed bugs to commercially available juvenile hormone analogues (JHAs), the increasing evidence of environmental pollution, and risk of chemical exposure, we aimed to design an alternative compound for managing bed bug infestations. By transforming a naturally occurring monoterpene into its C4 elongated conjugate esters, novel compounds were successfully synthesized in one step. Moreover, their impact on the development and reproduction of bed bugs Cimex lectularius Linnaeus were tested.
Recommended Citation
Alqahtani, Moneerah J., "LATE-STAGE DIVERSIFICATION OF SELECT NATURAL PRODUCTS – NEW CHEMICAL ENTITIES WITH IMPROVED BIOLOGICAL ACTIVITIES" (2022). Electronic Theses and Dissertations. 2191.
https://egrove.olemiss.edu/etd/2191