Design, Syntheses and Studies of Novel Antituberculosis Agents

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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 mg/kg), low toxicity (at least 10x over effective dose), minimal drug-drug interactions, good aqueous solubility (>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.