Novel Quaternary Ammonium Compounds Derived from the Antimicrobial Natural Product Ianthelliformisamine C Restricted; Files Only

Abstract

Quaternary ammonium compounds (QACs) are a class of antimicrobials commonly used in hospital and household disinfectant and antiseptic products. During the COVID-19 pandemic, the usage of QACs has likely risen drastically due to increased cleaning and disinfection to slow the spread of SARS-CoV-2, leading to increased concentrations of QACs accumulating in the environment. This is concerning because bacteria can develop resistance to QACs if exposed to sub-inhibitory concentrations in the environment. QAC resistance is tied to the development and proliferation of resistance to clinical antibiotics, exacerbating the risk of antibiotic resistant infections. Combating the threats of QAC resistance and antibiotic resistance necessitates the development of novel QACs with increased efficacy against resistant pathogens and higher barriers to the development of resistance. Antibacterial natural products present opportune scaffolds for the development of novel QACs because of their diverse structures and the possibility for creating multicationic QACs and QACs with a dual mechanism of action. The aim of this project was to synthesize novel quaternary ammonium compounds derived from the marine natural product ianthelliformisamine C. Ianthelliformisamine C was synthesized in seven steps in 47% overall yield following a lengthy optimization of the final step, a challenging amide coupling with a difficult purification process. Preliminary results for the quaternization of ianthelliformisamine have been challenged by low reactivity, prompting changes in the synthetic route to the ultimate QAC analogs. Going forward, minimum inhibitory concentration and hemolysis assays will be performed on the QAC analogs to investigate their antibacterial activity and toxicity.

Table of Contents

1. Background: Quaternary Ammonium Compounds, COVID-19, and Antibiotic Resistance................ 1

1.1 Quaternary Ammonium Compounds.......................................................................................... 1

1.2 Disinfectant Usage During the SARS-Co-V-2 Pandemic................................................................ 1

1.3 Antimicrobial Resistance........................................................................................................... 2

1.4 Multicationic QACs................................................................................................................... 2

2. Ianthelliformisamine A and C and Antibacterial Natural Product-Derived QACs.............................. 3

2.1 Rationale for Exploring Natural Product-Derived QACs................................................................ 3

2.2 Ianthelliformisamine A and C: Bioactivity and Previous Work....................................................... 4

2.3 Analog Design for Ianthelliformisamine-derived QACs................................................................. 6

3. Synthesis of Ianthelliformisamine C............................................................................................. 7

3.1 Synthesis of Ester and Carboxylic Acid Precursors to Ianthelliformisamines A & C......................... 7

3.2 DCC and EDC Coupling Optimization.......................................................................................... 8

3.3 Exploration of Alternative Coupling Reagents............................................................................ 12

3.4 Exploration of Protected Spermine Derivatives to Improve Amide Coupling................................. 13

3.5 Exploration of Direct Amidation to form Ianthelliformisamines A and C...................................... 14

3.6 Optimization of Amide Formation Through an Acyl Chloride Intermediate.................................. 16

3.7 Optimization of Purification Methods For Ianthelliformisamine C............................................... 17

3.8 DIC Coupling to Synthesize Ianthelliformisamine C in High Yield............................................... 18

4. Quaternization of Ianthelliformisamine C and Future Work......................................................... 18

4.1 Preliminary Studies of the Quaternization of Ianthelliformisamine C ......................................... 19

4.2 Proposed Biological Studies...................................................................................................... 21

5. Experimental ............................................................................................................................ 22

5.1 General Procedures for the Synthesis of Ianthelliformisamine C .................................................. 22

5.2General Procedures for the Methylation and Alkylation of Spermine and

Ianthelliformisamine C .................................................................................................................. 26

5.3 General Procedures for the Optimization of the Synthesis of Ianthelliformisamine C .................... 32

5.4 Spectral Data ........................................................................................................................... 45

References..................................................................................................................................... 68

Figures, Schemes, and Tables

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About this Honors Thesis

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School	Emory College
Department	Chemistry
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Chemistry, Organic
Keyword	natural products antimicrobial resistance organic synthesis
Committee Chair / Thesis Advisor	Wuest, William, Emory University
Committee Members	Himes, Richard, Emory University Clennon, Julie, Emory University

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