8-Hydroxyquinoline: a privileged structure with a broad-ranging pharmacological potential

Song, Yuning; Xu, Hao; Chen, Wenmin; Zhan, Peng; Liu, Xinyong

doi:10.1039/c4md00284a

Cited by 176 publications

(119 citation statements)

References 67 publications

(73 reference statements)

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“…One notable exception is mycobacteria (2,8), against which 8HQ's Cu requirement for activity remained unobserved in previous studies (7,8). In this study, we were able to clearly demonstrate that in these previous experiments the Cu ion content of commercial Middlebrook 7H9 medium disguised the Cu ion dependency of 8HQ (Fig.…”

Section: Discussionsupporting

confidence: 67%

“…The metal-binding abilities of 8HQ and its derivatives are well established and in many, though not all, cases have been linked to their anticancer, neuroprotective, and antimicrobial activity (2). One notable exception is mycobacteria (2,8), against which 8HQ's Cu requirement for activity remained unobserved in previous studies (7,8).…”

Section: Discussionmentioning

confidence: 99%

“…However, a potential synergy between Cu or other physiologically relevant transition metal ions and the activity of 8HQs on M. tuberculosis is unknown and, to our surprise, was not elucidated in previous studies (3,8). Given the consideration of 8HQ as an established scaffold for the development of novel antimycobacterial agents (2,8) and the omnipresence of Cu ions in vivo (29,30), it is imperative to detail and understand the impact of transition metal ions on the activity of 8HQs against M. tuberculosis.…”

mentioning

confidence: 99%

“…One such promising molecule with a broad spectrum of activity and a high repurposing potential is 8-hydroxyquinoline (8HQ) (2). The activity of 8HQ and several of its derivatives against M. tuberculosis has already been investigated in vitro (3,4) and was successfully tested in both animal models (5) and humans (6).…”

mentioning

confidence: 99%

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8-Hydroxyquinolines Are Boosting Agents of Copper-Related Toxicity in Mycobacterium tuberculosis

Shah

Dalecki

Malalasekera

et al. 2016

Antimicrob Agents Chemother

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c Copper (Cu) ions are likely the most important immunological metal-related toxin utilized in controlling bacterial infections. Impairment of bacterial Cu resistance reduces viability within the host. Thus, pharmacological enhancement of Cu-mediated antibacterial toxicity may lead to novel strategies in drug discovery and development. Screening for Cu toxicity-enhancing antibacterial molecules identified 8-hydroxyquinoline (8HQ) to be a potent Cu-dependent bactericidal inhibitor of Mycobacterium tuberculosis. The MIC of 8HQ in the presence of Cu was 0.16 M for replicating and nonreplicating M. tuberculosis cells. We found 8HQ's activity to be dependent on the presence of extracellular Cu and to be related to an increase in cell-associated labile Cu ions. Both findings are consistent with 8HQ acting as a Cu ionophore. Accordingly, we identified the 1:1 complex of 8HQ and Cu to be its active form, with Zn, Fe, or Mn neither enhancing nor reducing its Cu-specific action. This is remarkable, considering that the respective metal complexes have nearly identical structures and geometries. Finally, we found 8HQ to kill M. tuberculosis selectively within infected primary macrophages. Given the stark Cu-dependent nature of 8HQ activity, this is the first piece of evidence that Cu ions within macrophages may bestow antibacterial properties to a Cu-dependent inhibitor of M. tuberculosis. In conclusion, our findings highlight the metal-binding ability of the 8-hydroxyquinoline scaffold to be a potential focus for future medicinal chemistry and highlight the potential of innate immunity-inspired screening platforms to reveal molecules with novel modes of action against M. tuberculosis.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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8-Hydroxyquinolines Are Boosting Agents of Copper-Related Toxicity in Mycobacterium tuberculosis

Shah

Dalecki

Malalasekera

et al. 2016

Antimicrob Agents Chemother

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“…By contrast, the propensity of privileged warheads to bind promiscuously to multiple targets can result in unexpected activities [60][61][62][63][64].…”

Section: Page 9 Of 30mentioning

confidence: 90%

Discovery of bioactive molecules from CuAAC click-chemistry-based combinatorial libraries

Wang

Huang

Liu

et al. 2016

Drug Discovery Today

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140

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Introduction

2018

Privileged Structures in Drug Discovery

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8-Hydroxyquinoline: a privileged structure with a broad-ranging pharmacological potential

Abstract: An overview of the broad-ranging pharmacological applications of 8-HQ derivatives.

Cited by 176 publications

References 67 publications

8-Hydroxyquinolines Are Boosting Agents of Copper-Related Toxicity in Mycobacterium tuberculosis

8-Hydroxyquinolines Are Boosting Agents of Copper-Related Toxicity in Mycobacterium tuberculosis

Discovery of bioactive molecules from CuAAC click-chemistry-based combinatorial libraries

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