# Design, Syntheses and Studies of Novel Antituberculosis Agents

> **NIH NIH R37** · UNIVERSITY OF NOTRE DAME · 2024 · $562,125

## Abstract

Tuberculosis (TB) is a highly contagious airborne pathogen that infects > 2 billion people, of whom
an estimated 1.5 million people per year are killed by the disease. The global spread of multi-drug
resistant (MDR), extensively-drug resistant (XDR), and totally drug resistant (TDR) strains of
tuberculosis emphasizes the great need for new effective treatments. This renewal/Merit Award
application capitalizes on the discovery of hits against two critical targets in Mycobacterium
tubersuolsis – the imidazo[1,2-a]pyridine-3-carboxamides and the imidazo[2,1-b]pyridine-5-
carboxamides that target QcrB and novel scaffolds that target complimentary BD oxidase –
and seeks to advance these to potential TB treatments. As the first to patent, prolifically publish,
and propose the mechanism of action for the imidazo[1,2-a]pyridine-3-carboxamide (IAPC) series,
we are the most experienced group to continue development of this series through primate
evaluation in preparation for clinical (human) studies. Additionally, we have disclosed the impressive
in vitro properties of imidazo[2,1-b]thiazole 5-carboxamide (IT) series a new promising, rationally
designed, scaffold we will continue to develop. This new class has low nanomolar antiTB activity
against H37Rv, multidrug resistant (MDR) and extreme drug resistant (XDR) Mtb as well as good in
vitro metabolism and in vivo exposure with greater lung to plasma ratios. Most recently, we have
discovered a small molecule inhibitor of cytochrome bd oxidase in Mtb. A functional redundancy
between the cytochrome bcc:aa3 and the cytochrome bd oxidase protects M. tuberculosis from the
preclinical imidazopyridine (Q203)-induced bacterial death, highlighting the attractiveness of the bd-
type terminal oxidase for drug development. Combination of our QcrB and bd oxidase inhibitor is
bactericidal against replicating, nutrient-starved and hypoxic antibiotic-tolerant mycobacteria and
showed increased efficacy in a mouse model of infection. These results indicate that further
complementary development of a compound scaffold inhibiting the cytochrome bd oxidase will
enhance the value of a drug combination targeting oxidative phosphorylation for treatment of
tuberculosis.
 Furthermore, all of these heterocyclic scaffolds (IAPC, IT and bd oxidase inhibitor) can be prepared
in bulk (50 – 100 g) inexpensively and, from these penultimate intermediates, lead compounds with
animal efficacy can be prepared in just one synthetic step (amide bond formation or nucleophilic
aromatic substitution) and in multi-gram quantities (>15 g). Through our extensive collaborations,
we will evaluate all samples and combinations for antiTB activity. We will also perform related
studies, including microbe selectivity, gross toxicity particularly looking to avoid mitochondrial
toxicity, metabolism, pharmacokinetics (PK), maximum tolerated dose (MTD), mice and/or monkey
efficacy and mode of action studies of any new compounds with promising activity and
physic...

## Key facts

- **NIH application ID:** 10888366
- **Project number:** 5R37AI054193-18
- **Recipient organization:** UNIVERSITY OF NOTRE DAME
- **Principal Investigator:** MARVIN J MILLER
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $562,125
- **Award type:** 5
- **Project period:** 2021-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10888366

## Citation

> US National Institutes of Health, RePORTER application 10888366, Design, Syntheses and Studies of Novel Antituberculosis Agents (5R37AI054193-18). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10888366. Licensed CC0.

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