Graduation Year

2023

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Chemistry

Major Professor

James Leahy, Ph.D.

Committee Member

Edward Turos, Ph.D.

Committee Member

Lee Woodcock, Ph.D.

Committee Member

Robert Deschenes, Ph.D.

Keywords

Plasmodium, malaria, cannabinoids, total synthesis, avibactam, ß-lactamase inhibitors

Abstract

Modern medicine’s ability to treat a wide array of diseases is due mainly to the development of small-molecule drug discovery. Thousands of years of traditional medicines have been dwarfed in less than a hundred years. In addition, drug discovery has becoming a more consistent process with the introduction of the clinical trials process as well.Plasmodium is a genus of tropical parasites that have the potential to wreak havoc on billions of people globally. Current methods of drug discovery aimed at defeating these parasites require expensive assays that use radioactive material. By using an alkyne-labeled agent instead of a tritium-labeled agent, there is potential to replace the current standard with a cheaper and safer alternative. Novel purine analogs are synthesized using a Sonogashira coupling to attach a terminal alkyne to halogenated purines. The use of ethynyl-labeled purines shows efficacy as a direct replacement for tritium-labeled hypoxanthine. Data acquisition is also improved to prevent destruction of samples and allow for imaging. Recent discoveries involving the endocannabinoid system and its most dominant receptors have led to countless new avenues of research and drug development. The phytocannabinoids, while tempting to use directly, are prime targets for drug development due to their myriad of positive effects in the treatment of many illnesses. At the same time, it is possible that some of the drawbacks to these molecules can be overcome, such as their promiscuity and instability. A novel synthesis has been developed that utilizes a chiral, advanced intermediate to allow for diverse analog development. Analogs of tetrahydrocannabinol are synthesized to improve the stability and potential selectivity when interacting with endocannabinoid receptors. Synthesis of a molecular tool that can allow for the selective identification of other endocannabinoid-related receptors is also shown. Without doubt, one of the biggest issues that medicine must face in the modern era is the development of antibiotic resistant bacteria. Drugs that have been used for decades to treat infections have dwindled in efficacy as these bacteria adapt and evolve to survive these treatments. It should be noted that many classes of antibiotics share a ß-lactam core that is central to their activity and resistance. Unfortunately, many infectious species have developed ß-lactamse enzymes that destroy these cores and inactivate the drug. Of course, inhibitors for this effect have been used for decades, but still contain the same ß-lactam core. A new scaffold has been introduced that mimics the inhibitory activity while not containing a ß-lactam core. Approved by the FDA in 2015, avibactam has rapidly become the focus of a lot of antibiotic research. A new method of synthesis of the main avibactam core structure is proposed here. The synthesis is designed to be modular and convergent to allow for the use of varied agents to create new scaffolds. The analog development that can result from these new scaffolds has the potential to increase activity and versatility in the ß-lactamase inhibitor space.

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