Quinolinyl Pyrimidines: Potent Inhibitors of NDH-2 as a Novel Class of Anti-TB Agents

Shirude, Pravin S.; Paul, Beena; Choudhury, Nilanjana Roy; Kedari, Chaitanya Kumar; Bandodkar, Balachandra; Ugarkar, Bheemarao G.

doi:10.1021/ml300134b

Cited by 75 publications

(74 citation statements)

References 21 publications

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“…Several classes of compounds are proposed to target the enzyme at micromolar concentrations (e.g. phenothiazine analogues, platanetin, quinolinyl pyrimidines) (12, 27, 33), but the mechanism of inhibition remains unknown. Despite poor in vitro activity, drugs of the phenothiazine family (trifluoroperazine, chlorpromazine) have potent activity in vitro against drug-susceptible and drug-resistant M. tuberculosis strains (34, 35).…”

Section: Proton-pumping Type I Nadh Dehydrogenase and Non-proton Pumpmentioning

confidence: 99%

Energetics of Respiration and Oxidative Phosphorylation in Mycobacteria

et al. 2014

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Mycobacteria inhabit a wide range of intracellular and extracellular environments. Many of these environments are highly dynamic and therefore mycobacteria are faced with the constant challenge of redirecting their metabolic activity to be commensurate with either replicative growth or a non-replicative quiescence. A fundamental feature in this adaptation is the ability of mycobacteria to respire, regenerate reducing equivalents and generate ATP via oxidative phosphorylation. Mycobacteria harbor multiple primary dehydrogenases to fuel the electron transport chain and two terminal respiratory oxidases, an aa3-type cytochrome c oxidase and cytochrome bd-type menaquinol oxidase, are present for dioxygen reduction coupled to the generation of a protonmotive force. Hypoxia leads to the downregulation of key respiratory complexes, but the molecular mechanisms regulating this expression are unknown. Despite being obligate aerobes, mycobacteria have the ability to metabolize in the absence of oxygen and a number of reductases are present to facilitate the turnover of reducing equivalents under these conditions (e.g. nitrate reductase, succinate dehydrogenase/fumarate reductase). Hydrogenases and ferredoxins are also present in the genomes of mycobacteria suggesting the ability of these bacteria to adapt to an anaerobic-type of metabolism in the absence of oxygen. ATP synthesis by the membrane-bound F1FO-ATP synthase is essential for growing and non-growing mycobacteria and the enzyme is able to function over a wide range of protonmotive force values (aerobic to hypoxic). The discovery of lead compounds that target respiration and oxidative phosphorylation in Mycobacterium tuberculosis highlights the importance of this area for the generation of new front line drugs to combat tuberculosis.

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Section: Proton-pumping Type I Nadh Dehydrogenase and Non-proton Pumpmentioning

confidence: 99%

Energetics of Respiration and Oxidative Phosphorylation in Mycobacteria

et al. 2014

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“…Hence, drugs targeted to the aerobic respiratory chain should be considered, particularly when pathogens have respiratory enzymes that are distinctly different from those in the mitochrondrion. This is the case for the type-2 NADH dehydrogenase, or NDH-2, which is an important respiratory component in a number of pathogens but not present in the mammalian mitochondrial respiratory chain [14, 16, 18, 19]. Indeed, NDH-2 is actively being pursued as a possible drug target against Mycobacterium tuberculosis [14-17], Plasmodium falciparum [18] and Toxoplama gondii [13, 19].…”

Section: Discussionmentioning

confidence: 99%

Characterization of the type 2 NADH:menaquinone oxidoreductases from Staphylococcus aureus and the bactericidal action of phenothiazines

Schurig-Briccio

Yano

Rubin

et al. 2014

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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Methicillin-resistant Staphylococcus aureus (MRSA) is currently one of the principal multiply resistant bacterial pathogens causing serious infections, many of which are life-threatening. Consequently, new therapeutic targets are required to combat such infections. In the current work, we explore the type 2 NADH dehydrogenases (NDH-2s) as possible drug targets and look at the effects of phenothiazines, known to inhibit NDH-2 from Mycobacterium tuberculosis. NDH-2s are monotopic membrane proteins that catalyze the transfer of electrons from NADH via FAD to the quinone pool. They are required for maintaining the NADH/NAD+ redox balance and contribute indirectly to the generation of proton motive force. NDH-2s are not present in mammals, but are the only form of respiratory NADH dehydrogenase in several pathogens, including S. aureus. In this work, the two putative ndh genes present in the S. aureus genome were identified, cloned and expressed, and the proteins purified and characterized. Phenothiazines were shown to inhibit both of the S. aureus NDH-2s with IC50 values as low as 8 μM. However, evaluating the effects of phenothiazines on whole cells of S. aureus was complicated by the fact that they are also acting as uncouplers of oxidative phosphorylation.

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“…Além disso, essa molécula apresentou propriedades farmacocinéticas adequadas in vitro, as quais permitiram identificá-la como um importante protótipo anti-TB. 89 …”

Section: Alvos Envolvidos Com a Geração De Energiaunclassified

Potenciais alvos moleculares para o desenvolvimento de novos fármacos antituberculose

2017

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POTENTIAL MOLECULAR TARGETS FOR ANTITUBERCULOSIS DRUG DISCOVERY. Tuberculosis (TB) is an infectious disease caused by mycobacteria from the Mycobacterium genus, mainly by Mycobacterium tuberculosis (MTB). The World HealthOrganization (WHO) aims to reduce the number of TB cases worldwide in the coming years. Nevertheless, the increasing number of multidrug-resistant (MDR-TB) and extensive-drug resistance (XDR-TB) strains, and the ineffectiveness of the current treatment in latent tuberculosis are challenges to be overcome. In this review, we will demonstrate the recent advances in the tuberculosis drug discovery, focusing the research of new molecular targets in the Mycobacterium tuberculosis. Among the promising targets described herein, we highlight those, which act in different pathways in the mycobacteria, such as energy metabolism, cell wall biosynthesis, DNA synthesis, iron metabolism and transport through membranes. Furthermore, bioactive compounds discovered using phenotypic assays screening and validated through genetic approaches are also presented.Keywords: medicinal chemistry; tuberculosis; Mycobacterium tuberculosis; molecular targets; new drugs. INTRODUÇÃOA tuberculose (TB) é uma doença infecciosa causada por micobactérias do complexo Mycobacterium, no entanto, a espécie responsável pelo maior número de casos de morbidade e mortalidade é o Mycobacterium tuberculosis (MTB). 1 Ocupando o ranking mundial como a principal causa de mortes causadas por doenças infecciosas, nos últimos anos a tuberculose ultrapassou, em número de casos, a infecção causada pelo vírus da imunodeficiência humana (HIV). 2,3 O último levantamento realizado em 2015 pela Organização Mundial da Saúde (OMS) apontou 9.6 milhões de novos casos no mundo e 1.5 milhões de mortes causadas pela doença. 3 Somado a esses dados, o surgimento e aumento de cepas de M. tuberculosis multirresistente aos fármacos (MDR-TB) e extensivamente resistente aos fármacos (XDR-TB) vêm alarmando as autoridades de todo o mundo. Essas formas de tuberculose apresentam baixas taxas de cura e maiores taxas de mortalidade devido às dificuldades de tratamento. 4 Além disso, já foram relatados na clínica casos de tuberculose totalmente resistente aos fármacos (TDR-TB). 5,6 Ao longo dos últimos anos, é possível constatar algumas evoluções no desenvolvimento de compostos candidatos a fármacos que possam atuar contra a TB. 7 Após um intervalo de mais de 50 anos sem novos medicamentos para o tratamento da TB, a bedaquilina foi aprovada em 2012 pela agência norte-americana U.S. Food and Drug Administration (FDA) para o tratamento de MDR-TB. Atualmente, diversos candidatos a fármacos estão em estudos clínicos, [8][9][10][11][12] 39 Atualmente, diversos métodos e estratégias são utilizados para o desenvolvimento de novos fármacos contra a TB, como por exemplo: 1) abordagens genéticas para identificação de novos alvos; 2) ensaios de triagem em larga escala utilizando a micobactéria como plataforma; 3) ferramentas de biologia estrutural e triagem virtual e; 4) modificações ...

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Quinolinyl Pyrimidines: Potent Inhibitors of NDH-2 as a Novel Class of Anti-TB Agents

Cited by 75 publications

References 21 publications

Energetics of Respiration and Oxidative Phosphorylation in Mycobacteria

Energetics of Respiration and Oxidative Phosphorylation in Mycobacteria

Characterization of the type 2 NADH:menaquinone oxidoreductases from Staphylococcus aureus and the bactericidal action of phenothiazines

Potenciais alvos moleculares para o desenvolvimento de novos fármacos antituberculose

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