BRIDGING COMPLEXITY AND THERAPEUTICS: TOTAL SYNTHESIS OF LIMONOID NATURAL PRODUCTS AND DEVELOPMENT OF NOVEL ANTIBACTERIAL SULFA-DRUGS

Pillai, Vineet

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https://hdl.handle.net/2142/128069 Copy

Description

Title

BRIDGING COMPLEXITY AND THERAPEUTICS: TOTAL SYNTHESIS OF LIMONOID NATURAL PRODUCTS AND DEVELOPMENT OF NOVEL ANTIBACTERIAL SULFA-DRUGS

Author(s)

Pillai, Vineet

Issue Date

2025-05-07

Director of Research (if dissertation) or Advisor (if thesis)

Hergenrother, Paul

Department of Study

Chemistry

Discipline

Organic Chemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

B.S. (bachelor's)

Degree Level

Thesis

Date of Ingest

2025-05-08T13:29:14-05:00

Keyword(s)

NIMBOLIDE, BORYLATIVE HECK, SYNERGY, SULFA-DRUGS

Language

eng

Abstract

Natural product synthesis represents some of the most challenging problems facing organic chemistry today. Many natural products isolated in recent history have shown some novel and unprecedented biological activity, and with increasingly low isolation yields, the need for laboratory synthesis to produce these compounds has become an imperative need in the field of medicine today. Further, with increasing drug resistances in many bacterial strains, particularly in gram-negative pathogens, a means for novel ways to fight these infections has become a forefront of medicinal chemistry around the world. The first chapter of this document details the development and optimization of a synthetic route towards 4-epinimbin, an unnatural product and close derivative of a potent anticancer drug, nimbolide. Throughout these studies, we have developed a novel palladium-catalyzed borylative Heck reaction to easily access both diastereomers of a trans-decalin system, with oxidation at the C4 position, for 4-epinimbin and nimbolide. A ring-by-ring functionalization strategy was used to prepare the western fragment of the molecule, and through a key etherification reaction, the eastern fragment was introduced. Finally, radical cyclization and acetate protection provided 4-epinimbin in an 18-step sequence. The second chapter of this work describes the development of sulfa drugs that aim to act synergistically with an antipseudomonal trimethoprim analogue. Bactrim is a well-known drug combination of sulfamethoxazole and trimethoprim, used to treat Gram-negative infections. To tailor this study towards a more specific and prominent issue in medicine today, we hoped to make sulfa drugs which adhere to the PASsagE rules of Pseudomonas aeruginosa like the synthesized trimethoprim analogue, to increase compound potency in a historically challenging pathogen. As a part of this study, deep investigations were completed to test substrate compliance to certain conditions. Many synthetic pathways were tested to arrive at a collection of thirty biologically distinct compounds, three of which were made by my own efforts. Through a simple three step sequence involving an amide coupling reaction, a nitro reduction, and a Boc group deprotection, we arrived at three compounds which were tested against three bacterial strains through a chequerboard assay model. Although no promising biological activity was found throughout the study of the three synthesized compounds, this work provides foundational knowledge for the structure activity relationships for sulfa drugs in Pseudomonas aeruginosa.

Type of Resource

text

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