Rational Design, Synthesis, and Biological Evaluation of Heterocyclic Quinolones Targeting the Respiratory Chain of <i>Mycobacterium tuberculosis</i>

Hong, W. David; Gibbons, Peter; Leung, Suet C.; Amewu, Richard K.; Stocks, Paul A.; Stachulski, Andrew V.; Horta, Pedro; Cristiano, Maria Lurdes Santos; Shone, Alison E.; Moss, Darren M.; Ardrey, Alison; Sharma, Raman; Warman, Ashley J.; Bedingfield, Paul T. P.; Fisher, Nicholas; Aljayyoussi, Ghaith; Mead, Sally; Caws, Maxine; Berry, Neil G.; Ward, Stephen A.; Biagini, Giancarlo A.; O’Neill, Paul M.; Nixon, Gemma L.

doi:10.1021/acs.jmedchem.6b01718

Cited by 44 publications

(36 citation statements)

References 60 publications

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“…Because redox homeostasis is important for the survival of cells in a slowing-replicating state (27,28), Ndh inhibitors might also be good candidates to target persister or dormant Mtb bacteria. In that context, new Ndh inhibitors have been synthesized and shown to have antimycobacterial activity under aerobic and hypoxic conditions against both drug-susceptible and drug-resistant Mtb strains (29). Furthermore, redox homeostasis is also an important factor in drug activity and resistance, since many drugs against Mtb are prodrugs activated via a reductive process.…”

Section: Discussionmentioning

confidence: 99%

Plasticity of Mycobacterium tuberculosis NADH dehydrogenases and their role in virulence

Vilchèze

Weinrick

Leung³

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Worldwide control of the tuberculosis (TB) epidemic has not been achieved, and the latest statistics show that the TB problem might be more endemic than previously thought. Although drugs and a TB vaccine are available, TB eradication faces the challenges of increasing occurrences of multidrug-resistant and extensively drug-resistant () strains. To forestall this trend, the development of drugs targeting novel pathways is actively pursued. Recently, enzymes of the electron transport chain (ETC) have been determined to be the targets of potent antimycobacterial drugs such as bedaquiline. We focused on the three NADH dehydrogenases (Ndh, NdhA, and Nuo) of the ETC with the purpose of defining their role and essentiality in Each NADH dehydrogenase was deleted in both virulent and BSL2-approved strains, from which the double knockouts ΔΔ and ΔΔ were constructed. The ΔΔ double knockout could not be obtained, suggesting that at least one type II NADH dehydrogenase is required for growth. Δ and ΔΔ showed growth defects in vitro and in vivo, susceptibility to oxidative stress, and redox alterations, while the phenotypes of Δ Δ, and ΔΔ were similar to the parental strain. Interestingly, although Δ had no phenotype in vivo, ΔΔ was the most severely attenuated strain in mice, suggesting a key role for Nuo in vivo when Ndh is absent. We conclude that Ndh is the main NADH dehydrogenase of and that compounds that could target both Ndh and Nuo would be good candidates for TB drug development.

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Section: Discussionmentioning

confidence: 99%

Plasticity of Mycobacterium tuberculosis NADH dehydrogenases and their role in virulence

Vilchèze

Weinrick

Leung³

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…[1][2][3] In particular,t he synthesis of the fluoroquinolone family of compounds has made ag reat contribution to anti-infective agents, such as norfloxacin,c iprofloxacin, levofloxacin, and moxifloxacin. [4,5] The antimicrobialm echanism revealed that this type of drug could target DNA gyrase or topoisomerase IV by binding with enzyme-DNAb inaryc omplexes to form ternary supramolecular complexes, therebyo bstructing DNA replication and finally resulting in bacterial death. [6][7][8] However, the overuse of quinolones to manage bacterial infections has led to the evolution and widespread distribution of resistant strains,s uch as Streptococcus pneumoniae, Escherichia coli,a nd Staphylococcus aureus.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Benzimidazole–Quinolone Hybrids as New Cleaving Agents toward Drug‐Resistant Pseudomonas aeruginosa DNA

et al. 2018

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A series of benzimidazole-quinolone hybrids as new potential antimicrobial agents were designed and synthesized. Bioactive assays indicated that some of the prepared compounds exhibited potent antibacterial and antifungal activities. Notably, 2-fluorobenzyl derivative 5 b (ethyl 7-chloro-6-fluoro-1-[[1-[(2-fluorophenyl)methyl]benzimidazol-2-yl]methyl]-4-oxo-quinoline-3-carboxylate) showed remarkable antimicrobial activity against resistant Pseudomonas aeruginosa and Candida tropicalis isolated from infected patients. Active molecule 5 b could not only rapidly kill the tested strains, but also exhibit low toxicity toward Hep-2 cells. It was more difficult to trigger the development of bacterial resistance of P. aeruginosa against 5 b than that against norfloxacin. Molecular docking demonstrated that 5 b could effectively bind with topoisomerase IV-DNA complexes, and quantum chemical studies theoretically elucidated the good antimicrobial activity of compound 5 b. Preliminary experimental reaction mechanism exploration suggested that derivative 5 b could not intercalate into DNA isolated from drug-resistant P. aeruginosa, but was able to cleave DNA effectively, which might further block DNA replication to exert powerful bioactivities. In addition, compound 5 b is a promising antibacterial agent with membrane disruption abilities.

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“…This compound compares favorably with the most advanced inhibitors from two recently described medicinal chemistry efforts targeting Ndh-2: quinolinyl pyrimidines and a quinolone series. [8] The MIC 50 values of the most potent compounds from either of these two series ranged from 0.14–1.0 μM. Likewise, no compounds from a suite of phenothiazine-derived compounds gave MIC 50 values below 10 μM against aerobic Mtb.…”

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confidence: 99%

Small Molecules Targeting Mycobacterium tuberculosis Type II NADH Dehydrogenase Exhibit Antimycobacterial Activity

et al. 2018

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The generation of ATP through oxidative phosphorylation is an essential metabolic function for Mycobaterium tuberculosis (Mtb), regardless of the growth environment. The type II NADH dehydrogenase (Ndh-2) is the conduit for electrons into the pathway, and is absent in the mammalian genome, thus making it a potential drug target. Herein, we report the identification of two types of small molecules as selective inhibitors for Ndh-2 through a multicomponent high-throughput screen. Both compounds block ATP synthesis, lead to effects consistent with loss of NADH turnover, and importantly, exert bactericidal activity against Mtb. Extensive medicinal chemistry optimization afforded the best analogue with an MIC of 90 nM against Mtb. Moreover, the two scaffolds have differential inhibitory activities against the two homologous Ndh-2 enzymes in Mtb, which will allow precise control over Ndh-2 function in Mtb to facilitate the assessment of this anti-TB drug target.

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Rational Design, Synthesis, and Biological Evaluation of Heterocyclic Quinolones Targeting the Respiratory Chain of Mycobacterium tuberculosis

Cited by 44 publications

References 60 publications

Plasticity of Mycobacterium tuberculosis NADH dehydrogenases and their role in virulence

Plasticity of Mycobacterium tuberculosis NADH dehydrogenases and their role in virulence

Discovery of Benzimidazole–Quinolone Hybrids as New Cleaving Agents toward Drug‐Resistant Pseudomonas aeruginosa DNA

Small Molecules Targeting Mycobacterium tuberculosis Type II NADH Dehydrogenase Exhibit Antimycobacterial Activity

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