The biological inorganic chemistry of zinc ions.

8-Hydroxyquinolines in medicinal chemistry: A structural perspective.

Copper is a ubiquitous element in the environment as well as living organisms, with its redox capabilities and complexation potential making it indispensable for many cellular functions. However, these same properties can be highly detrimental to prokaryotes and eukaryotes when not properly controlled, damaging many biomolecules including DNA, lipids, and proteins. To restrict free copper concentrations, all bacteria have developed mechanisms of resistance, sequestering and effluxing labile copper to minimize its deleterious effects. This weakness is actively exploited by phagocytes, which utilize a copper burst to destroy pathogens. Though administration of free copper is an unreasonable therapeutic antimicrobial itself, due to insufficient selectivity between host and pathogen, small-molecule ligands may provide an opportunity for therapeutic mimicry of the immune system. By modulating cellular entry, complex stability, resistance evasion, and target selectivity, ligand/metal coordination complexes can synergistically result in high levels of antibacterial activity. Several established therapeutic drugs, such as disulfiram and pyrithione, display remarkable copper-dependent inhibitory activity. These findings have led to development of new drug discovery techniques, using copper ions as the focal point. High-throughput screens for copper-dependent inhibitors against Mycobacterium tuberculosis and Staphylococcus aureus uncovered several new compounds, including a new class of inhibitors, the NNSNs. In this review, we highlight the microbial biology of copper, its antibacterial activities, and mechanisms to discover new inhibitors that synergize with copper.

Copper and Antibiotics: Discovery, Modes of Action, and Opportunities for Medicinal Applications.

Iron, copper and zinc are required nutrients for many organisms but also potent toxins if misappropriated. An overload of any of these metals can be cytotoxic and ultimately lead to organ failure, whereas deficiencies can result in anemia, weakened immune system function, and other medical conditions. Cellular metal imbalances have been implicated in neurodegenerative diseases, cancer and infection. It is therefore critical for living organisms to maintain careful control of both the total levels and subcellular distributions of these metals to maintain healthy function. This perspective explores several strategies envisioned to alter the bioavailability of metal ions by using synthetic metal-binding agents targeted for diseases where misappropriated metal ions are suspected of exacerbating cellular damage. Specifically, we discuss chemical properties that influence the pharmacological outcome of a subset of metal-binding agents known as ionophores, and review several examples that have shown multiple pharmacological activities in metal-related diseases, with a specific focus on copper.

Pharmacological activity of metal binding agents that alter copper bioavailability

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 μM 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.

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

IT has been shown that 8-hydroxyquinoline is not toxic for Staphylococcus aureus unless traces of iron (or copper) are present in the medium (Rubbo, Albert and Gibson, 1950). It was next shown that a large excess of either iron or oxine prevented a rapid bactericidal action. This led to the hypothesis that oxine gained access to the cells as a complex having one atom of the metal bound between two molecules of oxine (to be referred to briefly as the 1: 2 complex (XIII)); and that it exerted its toxic effect inside the cells in the form of the unsaturated complex which consists of one molecule of oxine bound to one atom of the metal (i.e., the 1: 1 complex (XII)) (Albert, Gibson and Rubbo, 1953). It will be noted that this hypothesis postulates that oxine acts within the cell, and not on the outside as the aminoacridines do (Albert, 1951). The present work was carried out to test that assumption by varying the lipophilic nature of oxine by means of suitable substituents in the molecule. It is generally agreed that in a series of related substances the ease of penetration through a cell membrane is proportional to the lipophilic nature of the substance (Davson and Danielli, 1943; Hober, 1945). This lipophilic nature can be conveniently measured in terms of oil/water partition coefficients. In the present work the coefficient of oxine has been lowered by the insertion of one or more ring-nitrogen atoms, and the coefficients of some of the resulting substances have been raised again by the insertion of alkyl groups. It will be shown that the antibacterial properties disappear as the coefficient is lowered, and re-appear when it is raised again. These facts provide support for the hypothesis that oxine acts inside the cell.

The Influence of Chemical Constitution on Antibacterial Activity. Part VII: The Site of Action of 8-Hydroxy-Quinoline (Oxine).

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The Influence of Chemical Constitution on Antibacterial Activity. Part VII: The Site of Action of 8-Hydroxy-Quinoline (Oxine).