PART I: SYNTHESIS OF PHENOLIC ANTIBACTERIALS AND NATURAL PRODUCTS PART II: RAPID ASSESSMENT OF HYDROGEN BONDING CAPACITY

1. 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 threat of bacteria evolving resistance to antibiotics, scientists are constantly looking for new classes of compounds to treat infectious diseases. The biphenolic analogs of honokiol that were most potent against oral bacteria had similar bioactivity against MRSA. However, all the compounds proved ineffective against A. baumannii. The 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 1.1 scaffold was optimized from the inhibition of Gram-positive bacteria to broad-spectrum antibacterial compounds that inhibit the dangerous Gram-negative pathogen A. baumannii.2. Forty-four analogs of honokiol, a compound with known antibacterial activity, especially with respect to oral bacteria, were synthesized to explore the structure-activity relationships against the ESKAPE pathogens. Compounds with high therapeutic indices (hemolysis20/MIC) were identified. In particular, ester-linked compounds that would be less environmentally durable than biaryl ether antibacterials such as the broadly used triclosan were found to be active. MRSA mutants could be generated against some, but not all, of the highly active compounds. Gene sequencing results, membrane permeability, intracellular sodium, and intracellular pH assays revealed overlapping mechanisms of action. 3. Clausenawallines A-K, a class of eleven hydroxycarbazole natural products, have shown biological effects in preliminary study. An improved total synthesis of clausenawalline D and the first total synthesis of clausenawalline I have been completed. Clausenawalline A, a hydroxycarbazole homodimer may be synthesized using vanadium catalysis previously developed by the Kozlowski group. A modified method for the heterocoupling of hydroxycarbazoles has been developed, and the total syntheses of clausenawallines A, C, and E is currently underway. 4. Hydrogen bonding is a key molecular interaction in biological processes, drug delivery, and catalysis. This report describes a high throughput UV-Vis spectroscopic method to measure hydrogen bonding capacity using a pyrazinone sensor. This colormetric sensor reversibly binds to a hydrogen bond donor, resulting in a blue shift as additional equivalents of donor are added. Titration with excess equivalents of donor is used to determine the binding coefficient, ln(Keq). Over 100 titrations were performed for a variety of biologically relevant compounds. This data enabled development of a multiple linear regression model that is capable of predicting 95% of ln(Keq) values within 1 unit, allowing for the estimation of hydrogen bonding affinity from a single measurement. To show the effectiveness of the single point measurements, hydrogen bond strengths were obtained for a set of carboxylic acid bioisosteres. The values from the single point measurements were validated with full titrations.

Author dc:creator

• Roenfanz, Hanna, Frances

Advisor dc:contributor.advisor

• Kozlowski, Marisa, C

• Chemistry

Language dc:language.iso

en

Repository record dc:identifier.uri

https://repository.upenn.edu/handle/20.500.14332/58985

OAI identifier oai:identifier

oai:repository.upenn.edu:20.500.14332/58985