Advancement of Imidazo[1,2-<i>a</i>]pyridines with Improved Pharmacokinetics and nM Activity vs. <i>Mycobacterium tuberculosis</i>

Moraski, Garrett C.; Markley, Lowell D.; Cramer, Jeffrey W.; Hipskind, Philip A.; Boshoff, Helena I.; Bailey, Mai A.; Alling, Torey; Ollinger, Juliane; Parish, Tanya; Miller, Marvin J.

doi:10.1021/ml400088y

Cited by 108 publications

(92 citation statements)

References 11 publications

(28 reference statements)

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“…More recent efforts have yielded a novel class of imidazo[1,2-a]pyridine amide (IPA) compounds (77,78) that prevent proliferation of M. tuberculosis by inhibition of the cytochrome bc 1 reductase complex in the mycobacterial respiratory chain (77, 79) (Fig. 1).…”

Section: Drugs That Target the Etcmentioning

confidence: 99%

Energy Metabolism and Drug Efflux in Mycobacterium tuberculosis

Black

Warren

Louw

et al. 2014

Antimicrob Agents Chemother

116

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cThe inherent drug susceptibility of microorganisms is determined by multiple factors, including growth state, the rate of drug diffusion into and out of the cell, and the intrinsic vulnerability of drug targets with regard to the corresponding antimicrobial agent. Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), remains a significant source of global morbidity and mortality, further exacerbated by its ability to readily evolve drug resistance. It is well accepted that drug resistance in M. tuberculosis is driven by the acquisition of chromosomal mutations in genes encoding drug targets/promoter regions; however, a comprehensive description of the molecular mechanisms that fuel drug resistance in the clinical setting is currently lacking. In this context, there is a growing body of evidence suggesting that active extrusion of drugs from the cell is critical for drug tolerance. M. tuberculosis encodes representatives of a diverse range of multidrug transporters, many of which are dependent on the proton motive force (PMF) or the availability of ATP. This suggests that energy metabolism and ATP production through the PMF, which is established by the electron transport chain (ETC), are critical in determining the drug susceptibility of M. tuberculosis. In this review, we detail advances in the study of the mycobacterial ETC and highlight drugs that target various components of the ETC. We provide an overview of some of the efflux pumps present in M. tuberculosis and their association, if any, with drug transport and concomitant effects on drug resistance. The implications of inhibiting drug extrusion, through the use of efflux pump inhibitors, are also discussed.

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Section: Drugs That Target the Etcmentioning

confidence: 99%

Energy Metabolism and Drug Efflux in Mycobacterium tuberculosis

Black

Warren

Louw

et al. 2014

Antimicrob Agents Chemother

116

102

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“…MAC infection is difficult to treat and has been shown to be resistant to many of the clinically used antituberculosis agents (7,8). We previously disclosed a novel family of compounds, imidazo[1,2-a]pyridine-3-carboxamides (IAPs), with potent activity against Mycobacterium tuberculosis (9)(10)(11)(12). The mechanism of action and anti-M. tuberculosis in vivo efficacy of this exciting new class has been documented by us and other groups (9,(13)(14)(15)(16).…”

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confidence: 99%

“…Six compounds having diverse PKs were selected and synthesized according to our published methods (9)(10)(11). Experimental data and information on all previously uncharacterized compounds (1, 2, and 6) can be found in the supplemental material.…”

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confidence: 99%

“…Mice received by oral gavage a single dose of compound 1 (at 10 and 100 mg/kg), compound 2 (at 100 mg/ kg), compound 3 (at 10 mg/kg), compound 4 (at 30 mg/kg), compound 5 (at 100 mg/kg), and compound 6 (at 10 and 100 mg/kg). Compounds were analyzed as previously described (10). Calculated parameters include clearance (CL), area under the concentration-time curve (AUC), half-life (t 1/2 ), maximum serum concentration (C max ), time to C max (T max ), bioavailability (%F), and percent drug fraction unbound in plasma (%fplasma).…”

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confidence: 99%

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Imidazo[1,2- a ]Pyridine-3-Carboxamides Are Active Antimicrobial Agents against Mycobacterium avium Infection In Vivo

Moraski

Cheng

Cho

et al. 2016

Antimicrob Agents Chemother

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A panel of six imidazo[1,2-a]pyridine-3-carboxamides (IAPs) were shown to have low-micromolar activity against Mycobacterium avium strains. Compound ND-10885 (compound 2) showed significant activity in the lung, spleen, and liver in a mouse M. avium infection model. A combined regimen consisting of ND-10885 (compound 2) and rifampin was additive in its anti-M. avium activity in the lung. Our data indicate that IAPs represent a new class of antibiotics that are active against M. avium and could potentially serve as an effective addition to a combined treatment regimen. The incidence of nontuberculous mycobacteria (NTM) infections has been increasing in the United States (1, 2). Mycobacterium avium complex (MAC), which consists of M. avium and M. intracellulare, is an important cause of pulmonary disease in individuals with underlying lung diseases, such as cystic fibrosis and chronic obstructive pulmonary disease, and is an opportunistic pathogen in immunocompromised patients (3, 4). Among the NTM species isolated from U.S. patients, 80% are classified as MAC (5). MAC is ubiquitous within the environment and is found in soil, treated or untreated water, house plumbing systems, and animals (6). MAC infection is difficult to treat and has been shown to be resistant to many of the clinically used antituberculosis agents (7,8). We previously disclosed a novel family of compounds, imidazo[1,2-a]pyridine-3-carboxamides (IAPs), with potent activity against Mycobacterium tuberculosis (9-12). The mechanism of action and anti-M. tuberculosis in vivo efficacy of this exciting new class has been documented by us and other groups (9, 13-16). Through a hit-to-lead optimization effort aided by the Lilly TB Drug Discovery Initiative (LTBDDI), additional IAP compounds (1 to 6) were generated and found to have encouraging in vivo pharmacokinetics (PK). Herein, we describe the activity of these latest analogs against M. avium both in vitro and in vivo.Activity of selected compounds in vitro. Six compounds having diverse PKs were selected and synthesized according to our published methods (9-11). Experimental data and information on all previously uncharacterized compounds (1, 2, and 6) can be found in the supplemental material. MIC studies were performed using a resazurin-based colorimetric assay and CFU quantification, as described previously (17). Screening the IAPs against M. avium strains 101 and 2151 using standard protocols indicated that they had moderate potency (Table 1). The activities of these compounds against M. avium (2.6 to 27.8 M, two strains) were limited relative to M. tuberculosis (see Table S1 in the supplemental material) but comparable to positive controls of clarithromycin and azithromycin (1.4 and 13.4 M, respectively). These compounds also had a good therapeutic window when screened against Vero cells (9) (Table S1).All six compounds were evaluated for their ability to kill or inhibit M. avium replication in vitro. Five out of six compounds were bactericidal or bacteriostatic (Fig. 1). Consistent with its M...

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“…5,6 Imidazo-[1,2-a]pyridine-3-carboxamides, compound 15 and derivatives for example, appear to be a new class of potent selective antituberculosis agents. 7,8 BKM-120 (16, Figure 2), currently under evaluation in human clinical trials as a phosphoinositide-3-kinase (PI3K) inhibitor, has a similar 4-N,N-dialkylaminopyridinyl scaffold as found in 4-N,N-dimethylaminopyridine (9). 9 The enzyme, PI3K, which exists in several isoforms, plays an important role in cancer cell growth, survival, angiogenesis and metathesis.…”

Section: Introductionmentioning

confidence: 99%

Vaporization, Sublimation Enthalpy, and Crystal Structures of Imidazo[1,2-a]pyrazine and Phthalazine

et al. 2015

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ABSTRACT:The vaporization enthalpy of imidazo [1,2-a]pyrazine is evaluated by correlation gas chromatography using two sets of standards and by transpiration. Vaporization enthalpies were evaluated using heterocyclic standards with dipole moments that vary from 0 to 3.0 D and using standards with dipole moments > 3.0 D. A value of (70.7 ± 1.0) kJ·mol −1 measured by transpiration compares to (67.9 ± 1.4) kJ·mol −1 measured by correlation gas chromatography using standards characterized by dipole moments > 3.0 D. The results suggest that imidazo[1,2-a]pyrazine is a member of this series of compounds whose vaporization enthalpies exceed those less polar heterocycles by a fairly constant amount, (6.9 ± 0.3) kJ·mol −1 , in this case by (5.9 ± 3.0) kJ·mol −1 using the less polar heterocycles. The crystal structures of phthalazine, another member of the polar series, and of imidazo[1,2-a]pyrazine were determined to examine whether π−π stacking, present in the solid state of two other members of the polar series, was a characteristic of this series. If present in the liquid, π−π stacking could offer a possible explanation for the vaporization enthalpy differences observed. The sublimation enthalpy of imidazo[1,2-a]pyrazine was also evaluated.

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Advancement of Imidazo[1,2-a]pyridines with Improved Pharmacokinetics and nM Activity vs. Mycobacterium tuberculosis

Cited by 108 publications

References 11 publications

Energy Metabolism and Drug Efflux in Mycobacterium tuberculosis

Energy Metabolism and Drug Efflux in Mycobacterium tuberculosis

Imidazo[1,2- a ]Pyridine-3-Carboxamides Are Active Antimicrobial Agents against Mycobacterium avium Infection In Vivo

Vaporization, Sublimation Enthalpy, and Crystal Structures of Imidazo[1,2-a]pyrazine and Phthalazine

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