Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Nitroxoline: Difference between pages

{{short description|Antibiotic chemical compound}}

{{Infobox drug

| verifiedrevid = 462262233

| IUPAC_name = 5-nitro-quinolin-8-ol

| image = Nitroxolin.svg

| legal_US = [[Investigational new drug|IND]]

| routes_of_administration =

| excretion =

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| UNII_Ref = {{fdacite|correct|FDA}}

| ChEMBL = 1454910

<!--Chemical data-->

'''Nitroxoline''' is an [[antibiotic]]<ref name="pmid7793877">{{cite journal | vauthors = Pelletier C, Prognon P, Bourlioux P | title = Roles of divalent cations and pH in mechanism of action of nitroxoline against Escherichia coli strains | journal = Antimicrobial Agents and Chemotherapy | volume = 39 | issue = 3 | pages = 707–713 | date = March 1995 | pmid = 7793877 | pmc = 162609 | doi = 10.1128/aac.39.3.707 }}</ref> that has been in use in Europe for about fifty years, and has proven to be very effective at combating [[biofilm]] infections. Nitroxoline was shown to cause a decrease in the biofilm density of ''[[P. aeruginosa]]'' infections, which would allow access to the infection by the immune system ''in vivo''.<ref>{{cite journal | vauthors = Sobke A, Klinger M, Hermann B, Sachse S, Nietzsche S, Makarewicz O, Keller PM, Pfister W, Straube E | display-authors = 6 | title = The urinary antibiotic 5-nitro-8-hydroxyquinoline (Nitroxoline) reduces the formation and induces the dispersal of Pseudomonas aeruginosa biofilms by chelation of iron and zinc | journal = Antimicrobial Agents and Chemotherapy | volume = 56 | issue = 11 | pages = 6021–6025 | date = November 2012 | pmid = 22926564 | pmc = 3486607 | doi = 10.1128/aac.01484-12 }}</ref> It was shown that nitroxoline functions by [[chelating]] Fe²⁺ and Zn²⁺ ions from the biofilm matrix; when Fe²⁺ and Zn²⁺ were reintroduced into the system, biofilm formation activity was restored. The biofilm degradation ability is comparable to [[EDTA]] derivatives, but this drug has a history of human use in clinical settings and therefore has a precedent with which to allow its use against “slimy” biofilm infections.

==Anticancer activity==

The chelating activities of nitroxoline have also been used in an anticancer setting. Nitroxoline has been shown to be more [[cytotoxic]] to [[HL60]], DHL-4, [[PANC-1]], and {{ill|A2780|zh|A2780}} cells lines than [[clioquinol]] and other [[8-hydroxyquinoline]] derivatives.<ref>{{cite journal | vauthors = Jiang H, Taggart JE, Zhang X, Benbrook DM, Lind SE, Ding WQ | title = Nitroxoline (8-hydroxy-5-nitroquinoline) is more a potent anti-cancer agent than clioquinol (5-chloro-7-iodo-8-quinoline) | journal = Cancer Letters | volume = 312 | issue = 1 | pages = 11–17 | date = December 2011 | pmid = 21899946 | pmc = 3395224 | doi = 10.1016/j.canlet.2011.06.032 }}</ref> It also demonstrated an increase in [[reactive oxygen species]] (ROS) production over controls, especially when Cu²⁺ was added. The ROS levels reached over 350% of the controls with addition of CuCl₂. The cytotoxicity production was markedly decreased with addition of ZnCl₂, indicating, based on this model, that nitroxoline is not a zinc chelator. Because the zinc chelating action of clioquinol has been associated with [[subacute myelo-optic neuropathy]], the use of nitroxoline as a cytotoxic drug in the treatment of cancers should not exhibit neurotoxic effects in humans, and ''in vivo'' trials on tumour xenografts in mice have not yielded any negative neurodegenerative effects.

Nitroxoline has been shown to [[Enzyme inhibitor|inhibit the enzymatic activity]] of [[cathepsin B]].<ref>{{cite journal | vauthors = Mirković B, Renko M, Turk S, Sosič I, Jevnikar Z, Obermajer N, Turk D, Gobec S, Kos J | display-authors = 6 | title = Novel mechanism of cathepsin B inhibition by antibiotic nitroxoline and related compounds | journal = ChemMedChem | volume = 6 | issue = 8 | pages = 1351–1356 | date = August 2011 | pmid = 21598397 | doi = 10.1002/cmdc.201100098 | s2cid = 2963633 }}</ref> Cathepsin B degrades extra-cellular membrane proteins in tumor cells, allowing them to proliferate more freely, and metastasize throughout the body. Nitroxoline was shown to be a noncompetitive, reversible inhibitor of these actions in MCF-10A neoT cells. The ''K''_i ([[dissociation constant]]) values it demonstrates are comparable to other reversible inhibitors of cathepsin B. This indicates that it may be a candidate for further trials as an anticancer drug, especially given its history as an antimicrobial agent and its well-known [[pharmacokinetic]] profile. The mechanism of action by which nitroxoline inhibits cathepsin B may also suggest that further research of noncovalent, noncompetitive inhibitors of cathepsin B could be warranted. In fact, it was recently shown that a balance exists between the potency and the kinetics of a molecule, reflected in the molecular weight, which must be optimized in order to create the best drug for inhibition of a target enzyme.<ref>{{cite journal | vauthors = Sosič I, Mirković B, Arenz K, Stefane B, Kos J, Gobec S | title = Development of new cathepsin B inhibitors: combining bioisosteric replacements and structure-based design to explore the structure-activity relationships of nitroxoline derivatives | journal = Journal of Medicinal Chemistry | volume = 56 | issue = 2 | pages = 521–533 | date = January 2013 | pmid = 23252745 | doi = 10.1021/jm301544x }}</ref> For example, a certain inhibitor may have a high affinity for an enzyme, but it may prove impractical to use in a clinical setting for treatment because of its size.

Nitroxoline and its analogues have also been shown to have [[antiangiogenic]] properties.<ref name="doi=10.1093/jnci/djq457">{{cite journal | vauthors = Shim JS, Matsui Y, Bhat S, Nacev BA, Xu J, Bhang HE, Dhara S, Han KC, Chong CR, Pomper MG, So A, Liu JO | display-authors = 6 | title = Effect of nitroxoline on angiogenesis and growth of human bladder cancer | journal = Journal of the National Cancer Institute | volume = 102 | issue = 24 | pages = 1855–1873 | date = December 2010 | pmid = 21088277 | pmc = 3001967 | doi = 10.1093/jnci/djq457 }}</ref> For example, nitroxoline inhibits [[METAP2|MetAP2]] activity, an enzyme associated with [[angiogenesis]], and [[HUVEC]] proliferation.<ref>{{cite journal | vauthors = Bhat S, Shim JS, Zhang F, Chong CR, Liu JO | title = Substituted oxines inhibit endothelial cell proliferation and angiogenesis | journal = Organic & Biomolecular Chemistry | volume = 10 | issue = 15 | pages = 2979–2992 | date = April 2012 | pmid = 22391578 | pmc = 3767132 | doi = 10.1039/C2OB06978D }}</ref> This is further evidence that nitroxoline would make an effective anticancer drug. With different derivatives of nitroxoline demonstrating various levels of inhibition, nitroxoline may also prove to be a novel starting point for future research into cancer treatment.

== ''Balamuthia'' infection ==

In 2018, nitroxoline was identified via a [[clinical metagenomic next-generation sequencing]] analysis as a compound that could be [[Drug repurposing|repurposed]] as an [[amoebicidal]] agent against ''[[Balamuthia mandrillaris]]'' which causes the fatal disease [[granulomatous amoebic encephalitis]] (GAE).<ref name="LaurieWhiteDeRisi2018">{{cite journal | vauthors = Laurie MT, White CV, Retallack H, Wu W, Moser MS, Sakanari JA, Ang K, Wilson C, Arkin MR, DeRisi JL | display-authors = 6 | title = Functional Assessment of 2,177 U.S. and International Drugs Identifies the Quinoline Nitroxoline as a Potent Amoebicidal Agent against the Pathogen ''Balamuthia mandrillaris'' | journal = mBio | volume = 9 | issue = 5 | date = October 2018 | pmid = 30377287 | pmc = 6212833 | doi = 10.1128/mBio.02051-18 }}</ref>

In 2021, a patient survived an infection of ''Balamuthia mandrillaris'' after treatment with nitroxoline.<ref name="Nitroxoline for GAE2">{{cite news | vauthors = Kornei K |title=Repurposed drug battles 'brain-eating' amoeba |date=2023 |publisher=Science | doi = 10.1126/science.adh0048 }}</ref><ref name="Spottiswoode Nitroxoline2">{{cite journal | vauthors = Spottiswoode N, Pet D, Kim A, Gruenberg K, Shah M, Ramachandran A, Laurie MT, Zia M, Fouassier C, Boutros CL, Lu R, Zhang Y, Servellita V, Bollen A, Chiu CY, Wilson MR, Valdivia L, DeRisi JL | display-authors = 6 | title = Successful Treatment of Balamuthia mandrillaris Granulomatous Amebic Encephalitis with Nitroxoline | journal = Emerging Infectious Diseases | volume = 29 | issue = 1 | pages = 197–201 | date = January 2023 | pmid = 36573629 | doi = 10.3201/eid2901.221531 | pmc = 9796214 }}</ref> The man had been given the recommended drug therapy of [[pentamidine]], [[sulfadiazine]], [[azithromycin]], [[fluconazole]], [[flucytosine]], and [[miltefosine]] but progressed negatively. Therefore the regime was complemented with nitroxoline which required the permission of the [[FDA]] as the drug isn't approved in the United States. The cerebral lesion shrank only one week later after the new drug was added and the man later recovered.<ref>{{cite web | url=https://www.microbe.tv/twip/twip-222/ | title=TWiP 222: Balamuthia in the brain with Natasha Spottiswoode | date=31 October 2023 }}</ref>

== References ==

{{Reflist|30em}}

{{Other antibacterials}}

[[Category:Quinolinols]]

[[Category:Nitroarenes]]

[[Category:Antiparasitic agents]]

[[Category:Antibiotics]]