Design, Syntheses and Studies of Novel Antituberculosis Agents

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

physicochemical attributes including metabolite identification. Our criteria for a clinical candidate

are: selective nanomolar potency against H37Rv and drug resistant Mtb, in vivo efficacy comparable

to first line drugs isoniazid and rifampicin (at a dose 100 g/mL) and synthetic

simplicity/cost effectiveness. A highly qualified team of coworkers and collaborators from

experienced laboratories has been assembled to accomplish the overarching goal of

providing the TB-research and biomedical communities a promising new anti-tb drug

treatment as well as validated new drug targtes (respiratory bc1 complex bd oxidase of Mtb).

RELEVANCE (See instructions):

Tuberculosis (TB) is a serious global health risk that infects more than 2,000,000,000

people worldwide and causes a death every 20 seconds! The objective of this proposal

is to develop cost effective anti-TB agents. The focus is on studies of new small

molecular weight compounds that are easily synthesized, non-toxic, and yet effective at

inhibiting TB growth.