# Indole Alkaloids and Phenazine Antibiotics: New Platforms for Drug Discovery

> **NIH NIH R35** · UNIVERSITY OF FLORIDA · 2020 · $347,746

## Abstract

Indole Alkaloids and Phenazine Antibiotics: New Platforms For Drug Discovery
Abstract:
New small molecule probes and therapeutic agents are critical for the study and treatment of human
disease. Our group is developing multiple chemical synthesis strategies to probe diverse biological
phenomena related to human disease, including: bacterial biofilm viability, GPCR function, cancer
biology and Plasmodium falciparum biology. We have developed a tryptoline-based ring distortion
strategy using commercially available indole alkaloids (yohimbine and vincamine) as starting points for
ring distortion, or the dramatic altering/reorganization of complex ring systems using chemoselective
reactions. This approach has enabled the rapid synthesis of highly complex and diverse scaffolds for
biological investigations and we have identified hit compounds in multiple disease-relevant areas
pertinent to human health. Our hit compounds have gained new biological functions as their biological
activities are unrelated to other scaffolds or their parent natural product, in essence, re-engineering of
indole alkaloid’s chemical scaffolds and biological functions have been demonstrated. During this award,
we will enhance the chemical diversity of our indole alkaloid ring distortion library by using C-H oxidation
chemistry to install new synthetic handles for ring distortion and diastereoselective oxidative
rearrangements to give new spirooxindole scaffolds with the ultimate goal of exploring disease-relevant
chemical space with our probe molecules. In addition, our group has identified a series of halogenated
phenazines (HP) that demonstrate potent biofilm-eradicating activities. These findings are significant as
bacterial biofilms, or surface-attached bacterial communities, house persistent, non-replicating bacteria
(persister cells) that demonstrate tolerance to all classes of antibiotics. Biofilms pose a significant threat
to human health as 17 million new biofilm-associated bacterial infections occur annually that result in
550,000 deaths in the United States. We aim to use the HP small molecules we have developed as
probe molecules in RNA-seq experiments with MRSA biofilms alongside other biofilm-killing agents to
investigate biofilm viability with the goal of identifying new targets and cellular pathways critical to
bacterial biofilms. In addition, we aim to develop a diverse array of HP prodrugs through chemical
synthesis and in vitro biological studies. Providing new insights into the basic biology critical to biofilm
cell viability and developing new biofilm-eradicating prodrugs could lead to ground-breaking cures for
persistent bacterial infections.
Huigens (PI) Project Summary/Abstract

## Key facts

- **NIH application ID:** 9983101
- **Project number:** 5R35GM128621-03
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Robert William Huigens
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $347,746
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983101

## Citation

> US National Institutes of Health, RePORTER application 9983101, Indole Alkaloids and Phenazine Antibiotics: New Platforms for Drug Discovery (5R35GM128621-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9983101. Licensed CC0.

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