4008-48-4

Usage

Uses

1. Used in Pharmaceutical Industry:
Nitroxoline is used as an antimicrobial agent for the treatment of urinary tract infections. It is also a potent and reversible inhibitor of cathepsin B and has demonstrated anti-cancer activity.
2. Used in Antimicrobial Applications:
Nitroxoline is effective against bacteria such as E. coli, S. aureus, E. faecalis, K. pneumoniae, and P. mirabilis in vitro. It also inhibits biofilm formation of certain strains of multidrug-resistant (MDR) A. baumannii and P. aeruginosa, as well as methicillin-resistant S. aureus (MRSA) and S. epidermidis (MRSE).
3. Used in Cancer Treatment:
Nitroxoline inhibits the growth of human U87 and U251 glioma, A549 lung, and PC3 prostate cancer cells. In vivo, it reduces tumor growth in a PTENand KRAS-driven glioma mouse model when administered at a dose of 80 mg/kg per day.
4. Used in Synthesis of Chelating Agents:
8-Hydroxy-5-nitroquinoline is used in the synthesis of novel CO2-soluble 8-hydroxyquinoline chelating agents.
5. Used in Bromodomain Inhibition:
Nitroxoline inhibits the interaction between the first bromodomain of bromodomain-containing protein 4 (BRD4) with acetylated histone H4 with an IC50 value of 0.98 μM.
Brand Names:
Some of the brand names for Nitroxoline include 5-nitrok, Dovenix, Entercol, Enterocol, Isinok, Nicene, Nikinol, Nikopet, Noxine, Trodax, and Uro-coli.

World Health Organization (WHO)

Nitroxoline, a urinary antiseptic, was introduced in the mid-1960s. By the early 1970s long-term animal studies revealed the development of cataracts in rats and, although no serious adverse effects had been reported in man, the drug was withdrawn in at least two countries. Preparations containing nitroxoline remain widely available.

Biochem/physiol Actions

8-Hydroxy-5-nitroquinoline is an effective anti-microbial and anti-cancer agent. It is an effective drug for the treatment of urinary tract infections due to gram negative bacilli.

in vitro

the machnistic study showed that nitroxoline, in the treatment of acute or recurrent urinary tract infections caused by escherichia coli, could be decreased in the presence of mg2+ and mn2+ but not ca2+. moreover, with the divalent metal ions, a shift in the nitroxoline a448 indicated the formation of drug-ion complexes and a clear correlation was observed between the chelating property and antibacterial activity of nitroxolinet. in addition, it was found that the uptake was energy-independent and with biphasic kinetics: a rapid cell association phase and then a slower increase of cell- nitroxoline association [1].

in vivo

previous animal study showed that nitroxoline suspension with tween-80 in a could decrease the tone of the rat and guinea-pig ileum and diminish their peristalsis. moreover, when administered orally in a dose 50 mg/kg to rats, nitroxoline was able to inhibit the agar-, serotonin-, as well as carrageenin-induced edemas of the rat paws without affecting the response to subplantar histamine injection [2].

references

[1] pelletier c,prognon p,bourlioux p. roles of divalent cations and ph in mechanism of action of nitroxoline against escherichia coli strains. antimicrob agents chemother.1995 mar;39(3):707-13.[2] zaks as,zil'ber al,kapitonenko ta. spasmolytic and anti-inflammatory activity of 8-hydroxyquinolines. farmakol toksikol.1984 sep-oct;47(5):44-7.[3] lambert-zechovsky n,lévêque b,bingen e,pillion g,chapelle j,mathieu h. clinical study and effect of nitroxoline on fecal flora in childrenpathol biol (paris).1987 may;35(5):669-72.

InChI:InChI=1/C9H6N2O3/c12-8-4-3-7(11(13)14)9-6(8)2-1-5-10-9/h1-5,12H

Upstream product

• 3565-26-2 5-nitroso-8-hydroxyquinoline 
• 56-81-5 glycerol 
• 99-57-0 2-hydroxy-5-nitroaniline 
• 42322-37-2 5-nitro-quinoline-8-yl acetate 
• 1555-94-8 8-ethoxyquinoline 
• 63450-86-2 5-Nitroso-8-hydroxyquinoline hydrochloride 
• 19746-57-7 8-ethoxy-5-nitroquinoline 
• 148-24-3 8-quinolinol 

Downstream Products

• 74440-56-5 7-diethylaminomethyl-5-nitro-quinolin-8-ol 
• 23521-17-7 7-bromo-8-hydroxy-5-nitroquinoline 
• 74440-55-4 5-nitro-7-(pyrrolidin-1-ylmethyl)quinolin-8-ol 
• 74440-54-3 5-nitro-7-(piperidin-1-ylmethyl)quinolin-8-ol 
• 74440-59-8 7-((4-methylpiperazin-1-yl)methyl)-5-nitroquinolin-8-ol 
• 76289-27-5 5-nitro-7-((4-phenylpiperazin-1-yl)methyl)quinolin-8-ol 
• 76289-25-3 5-Nitro-7-(2-hydroxyethylaminomethyl)-8-quinolinol 
• 76289-26-4 5-Nitro-7-(phenethylamino-methyl)-quinolin-8-ol 
• 74440-58-7 7-[(Diisopropylamino)-methyl]-5-nitro-quinolin-8-ol 
• 74440-57-6 7-{[Bis-(2-hydroxy-ethyl)-amino]-methyl}-5-nitro-quinolin-8-ol 
• 65741-91-5 5-Nitro-8-tosyloxyquinoline 
• 17012-47-4 8-methoxy-5-nitroquinoline 
• 21302-43-2 5-amino-8-hydroxyquinoline dihydrochloride 
• 160893-36-7 C₁₅H₉IN₂O₃ 

Relevant academic research and scientific papers

Synthesis, characterization, computational and biological study of novel azabenzo[a]phenothiazine and azabenzo[b]phenoxazine heterocycles as potential antibiotic agent

Two angular phenothiazines and one angular phenoxazine were successfully synthesized via anhydrous base condensation reaction of 2,6-diamino-4-chloropyrimidine-5-thiol, with 7-chloro-5,8-quinolinequinone,2-aminothiophenol and 2-aminophenol, respectively. Condensation reaction between 2-6-diamino-4-chloropyrimidine-5-thiol and 7-chloro-5,8-quinolinequinone in the presence of anhydrous sodium carbonate yielded 10-amino-8-chloro-1,9,11-triaza-5H-benze[a]phenothiazine-5-one, 1-aza-5H-benzo[a]phenothiazine-5-one and 1-aza-5H-benzo[a]phenoxazine-5-one were produced with anhydrous basic condensation between 7-chloro-5,8-quinolinequinone and 2-aminothiophenol and 2-aminophenol respectively. These angular azaphenothiazin-5-ones and angular azaphenoxazine-5-one were converted to their derivatives via palladium(o)/piperazine ligand utilizing Mizoroki–Heck cross coupling tandem reaction to obtain six derivatized compounds. The synthesized compounds are intensely coloured and their structural elucidation were established by combined spectroscopic and elemental analytical data. In silico and in vitro screening methods were used to investigate the antibacterial potencies of the compounds. All the compounds, except one, interacted with Type I SPase, an unconventional validated antibiotic enzyme targeted in combating antibacterial resistant, at low micromolar range. They also showed activity against the tested bacteria: Bacillus cereus, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa. In fact, B. cereus exhibited more susceptibility towards four of the compounds than the standard drug—ciprofloxacin. The predicted binding modes of four compounds with outstanding activities were finally studied to identify vital ligand–protein interactions, which can serve as template during activity optimization process.

Powder diffraction study of the hydrogen bonds in nitroxoline and its hydrochloride.

The crystal structures of 8-hydroxy-5-nitroquinoline, C9H6N2O3, (I), and 8-hydroxy-5-nitroquinolinium chloride, C9H7N2O3+*Cl-, (II), have been determined from X-ray powder data. In (I), the molecules are linked via moderately strong hydrogen bonds to form dimers. Such a packing motif is likely to be responsible for the low solubility of (I) in water. In (II), the inversion-related cations form stacks, and anions fill the interstack channels.

Design, synthesis, and evaluation of multitarget-directed selenium-containing clioquinol derivatives for the treatment of Alzheimer's disease

A series of selenium-containing clioquinol derivatives were designed, synthesized, and evaluated as multifunctional anti-Alzheimer's disease (AD) agents. In vitro examination showed that several target compounds exhibited activities such as inhibition of metal-induced Aβ aggregation, antioxidative properties, hydrogen peroxide scavenging, and the prevention of copper redox cycling. A parallel artificial membrane permeation assay indicated that selenium-containing clioquinol derivatives possessed significant blood-brain barrier (BBB) permeability. Compound 8a, with a propynylselanyl group linked to the oxine, demonstrated higher hydrogen peroxide scavenging and intracellular antioxidant activity than clioquinol. Furthermore, 8a exhibited significant inhibition of Cu(II)-induced Aβ1-42 aggregation and was capable of disassembling the preformed Cu(II)-induced Aβ aggregates. Therefore, 8a is an excellent multifunctional promising compound for development of novel drugs for AD. (Chemical Equation Presented).

Synthesis of 1-azabenzo[a]phenoxazin-5-one and 11-amino-1,8,10-triazabenzo[a]phenoxazin-5-one and their Functionalized aryl derivatives via Mizoroki-Heck arylation methodology

The synthesis of angular 1-azabenzo[a]phenoxazin-5-one and 11-amino-1,8,10-triazabenzo[a] phenoxazin-5-one and their functionalized aryl derivatives via Mizoroki-Heck arylation methodology is reported. 11-Amino-1,8,10-triazabenzo[a]phenoxazin-5-one (16) and 1-azabenzo[a]phenoxazin-5-one (18) were synthesized by the reaction of 7-chloro-5,8-quinolinequinone (obtained by a multistage conversion of 8-hydroxyquinoline) with 4,5-diamino-6-hydroxypyrimidine and 2-aminophenol respectively in the presence of anhydrous sodium acetate. 11-Amino-1,8,10-triazabenzo[a]phenoxazin-5-one and 1-azabenzo[a]phenoxazin-5-one were subjected to Mizoroki-Heck coupling reaction by refluxing with iodobenzene derivatives, using 1,4-bis(diphenylphosphino)butane-palladium(11) chloride as catalyst, 1,4-bis-(2-hydroxy-3,5-ditertbutylbenzyl)piperazine as ligand and methanol as solvent at 60-650C for 4 h to afford in excellent yield aryl derivatives of angular 11-amino-1,8,10-triazabenzo[a]phenoxazin-5-one (19a-c) and 1-azabenzo[a]phenoxazin-5-one (20a-c) respectively. The structures were established by UV/visible, FTIR, proton-NMR and carbon-13 NMR spectral and elemental analysis.

Synthesis and anti-phytopathogenic activity of 8-hydroxyquinoline derivatives

Phytopathogenic fungi have become a serious threat to the quality of agricultural products, food security and human health globally, necessitating the need to discover new antifungal agents with de novo chemical scaffolds and high efficiency. A series of 8-hydroxyquinoline derivatives were designed and synthesized, and their antifungal activity was evaluated against five phytopathogenic fungi. In vitro assays revealed that most of the tested compounds remarkably impacted the five target fungi and their inhibitory activities were better than that of the positive control azoxystrobin. Compound 2, in particular, exhibited the highest potency among all the tested compounds, with an EC50 of 0.0021, 0.0016, 0.0124, 0.0059 and 0.0120 mM respectively against B. cinerea, S. sclerotiorum, F. graminearum, F. oxysporum and M. oryzae, followed by compound 5c. The morphological observations of optical microscopy and scanning electron microscopy revealed that compounds 2 and 5c caused mycelial abnormalities of S. sclerotiorum. Futhermore, the results of in vivo antifungal activity of compounds 2 and 5c against S. sclerotiorum showed that 5c possessed stronger protective and curative activity than that of 2, and the curative effects of 5c at 40 and 80 μg mL-1 (84.18% and 95.44%) were better than those of azoxystrobin (77.32% and 83.59%). Therefore, compounds 2 and 5c are expected to be novel lead structures for the development of new fungicides.

Study on Relationship Between Fluorescence Properties and Structure of Substituted 8-Hydroxyquinoline Zinc Complexes

Organic light-emitting diodes (OLEDs) produced from 8-hydroxyquinoline metal complexes play a vital role in modern electroluminescent devices. In this manuscript, a series of 8-hydroxyquinoline derivatives were synthesized by different methods and their corresponding zinc metal complexes were prepared. The UV and fluorescence properties of the complexes were measured aiming to understand the effect of substituents at the quinoline ring on the fluorescence properties of the complexes. When the C-5 of 8-hydroxyquinoline was replaced by halogen group, the fluorescence emission wavelengths had been red-shifted, at the same time, blue-shifted of fluorescence emission wavelength was observed when the C-5 position of 8-hydroxyquinoline was substituted by electron-withdrawing group. When the C-4 position of 8-hydroxyquinolie was substituted by methyl or the C-5 position was substituted by sulfonic acid group, the corresponding zinc complexes had higher fluorescence intensity than 8-hydroxyquinolie zinc.

Palladium catalyzed transformation and antimicrobial screening of novel angular azaphenothiazines

Base mediated condensation reaction between 2-amino-5-bromopyrazine-3[4H]-thione and 7-chloro-5,8-quinolinequinone under anhydrous condition gave 9-bromo-1,8,11-triaza-5H-benzo[a]phenothiazin-5-one. Palladium catalyzed cross-coupling reaction between 9-bromo-1,8,11-triaza-5H-benzo[a]phenothiazin-5-one and four arylated halogeno compounds utilizing Heck-Mizoroki protocol furnished 6-substituted derivatives of the angular tetracyclic heterocycle. Structures were assigned based on spectroscopic and elemental analytical data. Antimicrobial screening of these compounds showed they were biologically active.

New Aryl Derivatives of Quinolinedione and Related Heterocyclic Compounds

The synthesis of new derivatives of 6,7-dibromoquinoline-5,8-dione and 6,7-dichloroquinoline-5,8-dione via palladium/Sphos-mediated Suzuki–Miyaura cross-coupling reaction is reported. The 6,7-dibromoquinoline-5,8-dione and 6,7-dichloroquinoline-5,8-dione intermediates were prepared in a three-step reaction from 8-hydroxyquinoline. The palladium-catalyzed reactions of 6,7-dibromoquinoline-5,8-dione and 6,7-dichloroquinoline-5,8-dione with a variety of aryl boronic acids provide coupled compounds in high yields. The arylation of 6,7-dibromoquinoline-5,8-dione and 6,7-dichloroquinoline-5,8-dione with 4-bromophenyl boronic acid supplied 6,6′-(1,4-phenylene)bis(7-bromoquinoline-5,8-dione) and (4-(6-(4-(6-chloro-5,8-dihydroquinolin-7-yl)phenyl)-5,8-dihydroquinolin-7-yl)phenyl)boronic acid respectively, in addition to the expected coupled compounds in moderate yields. Also, Pd(0)/PPh3 allowed the 7-chloro-6-(4-nitrophenyl)quinoline-5,8-dione and 7-chloro-6-phenylquinoline-5,8-dione to be synthesized via Heck reaction. The yields of the synthesized target molecules depend largely on the reaction conditions and the type of ligands employed. Structural assignments of the synthesized compounds were established by spectra and analytical data.

Design, synthesis and evaluation of clioquinol-ebselen hybrids as multi-target-directed ligands against Alzheimer's disease

A novel series of compounds obtained by fusing the metal-chelating agent clioquinol and the antioxidant ebselen were designed, synthesized and evaluated as multi-target-directed ligands against Alzheimer's disease (AD). Specifically, compared with their parent compounds clioquinol and ebselen, these hybrids demonstrated significant potency in inhibiting self- and Cu(ii)-induced amyloid-β (Aβ) aggregation and acted as remarkable antioxidants and biometal chelators. In addition, the hybrids showed considerable improvements in ebselen-related pharmacological properties, including the ability to mimic glutathione peroxidase and scavenge H2O2. Of these molecules, compound 10h was identified as a potential lead compound for AD therapy. Importantly, this compound was found to possess rapid H2O2 scavenging activity and glutathione peroxidase-like (GPx-like) activity. Moreover, compound 10h was able to efficiently disassemble preformed self- and Cu(ii)-induced Aβ aggregates. Furthermore, 10h was able to penetrate the central nervous system (CNS) and did not exhibit any acute toxicity in mice at doses up to 2000 mg kg-1.

Computer-assisted designed "selenoxy-chinolin": A new catalytic mechanism of the GPx-like cycle and inhibition of metal-free and metal-associated Aβ aggregation

Using support from rational computer-assisted design, a novel series of hybrids (selenoxy-chinolin) designed by fusing the metal-chelating agent CQ and the antioxidant ebselen were synthesized and evaluated as multitarget-directed ligands. Most of the hybrids demonstrated significant ability to mimic GPx, which is highly consistent with the prediction results of DFT studies for the selenenyl sulfide intermediates in the computational design. Using 77Se, 1H and 13C NMR spectroscopy and high-resolution mass spectroscopy (HRMS), a novel catalytic mechanism, including a new selenium quinone active species, was first demonstrated. 2D NMR studies indicated that the typical hybrid has an effective interaction with Aβ. In addition, the optimal compound 12k was found to possess an excellent ability to scavenge peroxide and to inhibit self- and metal-induced Aβ aggregation, and an ability to disassemble preformed self- and metal-induced Aβ aggregates effectively. Furthermore, 12k was able to penetrate the central nervous system (CNS) and did not exhibit any acute toxicity in mice at doses up to 2000 mg kg-1. Overall, we demonstrated that hybrid 12k, through rational structure-based computational design, shows a potential for development as a therapeutic agent in AD.