Date of Award

2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Chemistry

First Advisor

Marisa C. Kozlowski

Abstract

Part I: Oxidative insertion into C-H bonds is an important subfield of organic chemistry that allows for formation of new C-C bonds without prefunctionalization of the starting substrates, leading to more efficient synthesis. The mechanisms by which oxidative coupling occurs can vary amongst structurally similar phenols, such that there is no general catalyst that works with a broad range of phenols. By using an extensive library of catalysts to create profiles for groups of phenols that have similar reactivity, more efficient catalysts can be designed to perform oxidative coupling. Taking advantage of High Throughput Experimentation (HTE), 24 salen/salan chromium, copper, iron, manganese, ruthenium, and vanadium catalysts with a variety of previously unexplored steric and electronic effects were examined efficiently in the oxidative homo-coupling of a broad range of phenols. Amongst the set, several different reaction trends were observed. Notably, the groupings of catalysts with different metals were discovered to have similar reactivity profiles, allowing us to hypothesize that different metals catalysts may operate by similar mechanisms.

Part II: The naturally occurring bisphenol, honokiol, has been employed in traditional Chinese, Japanese, and Korean herbal medicine. Recent studies reported that honokiol has strong anti-bacterial properties against the oral bacteria Streptococcus mutans. A library of derivatives inspired by honokiol was generated using novel oxidative coupling developed in the Kozlowski laboratory, in order to improve and better understand its bioactivity. In these studies, the anti-bacterial properties of honokiol were found not to be as strong as previously reported. However, 12 honokiol- inspired analogs were synthesized that possessed equal or better inhibitory ability relative to honokiol.

Part III: From the library of honokiol analogs, 5,5’-(ethane-1,2-diyl)bis(2-(tert-butyl)phenol) (C2) was identified as highly potent against S. mutans planktonic cells. This new scaffold greatly improved upon the natural product, but it was unclear what structural features were causing this potent activity and what biological mechanism led to the effect. For this reason, 66 new analogs of C2 were designed to assess the structure-activity relationships (SAR) of the lead compound. Compound C2 and several of its closely related analogs were discovered to affect bacterial membrane stability and fluidity in S. mutans. Moreover, C2 has similar potency and an improved therapeutic index when compared to the commercially antimicrobial cetylpyridinium chloride.

Part IV: The gram-positive bacteria, methicillin-resistant Staphylococcus aureus (MRSA), and gram-negative bacteria, Acinetobacter baumannii, are pathogens responsible for millions of nosocomial infections worldwide. Due to the emerging threat of bacteria evolving resistance to more antibiotics, scientists are constantly looking for new classes of compounds that can treat infectious diseases. The bisphenolic analogs of honokiol that were most potent against oral bacteria had similar bioactivity against MRSA. However, all the compounds proved ineffective against A. baumannii. This inability to inhibit A. baumannii is due to the difficult-to-penetrate lipopolysaccharide-coated outer membrane that makes it challenging for antibiotics to enter gram-negative bacteria. The C2 scaffold was optimized from the inhibition of only gram-positive bacteria to broad-spectrum antibacterial compounds that inhibit the dangerous gram-negative pathogen A. baumannii.

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