965-52-6

Basic information

• Product Name: Nifuroxazide
• Synonyms: (nitro-5’furfurylidene-2’)hydroxy-4benzhydrazide;4-hydroxy-benzoicaci((5-nitro-2-furanyl)methylene)hydrazide;diarlidan;dicoferin;ercefurol;ercefuryl;nifuroxazid;p-hydroxy-benzoicaci(5-nitrofurfurylidene)hydrazide
• CAS NO: 965-52-6
• Molecular Formula: C₁₂H₉N₃O₅
• Molecular Weight: 275.22
• EINECS: 213-522-0
• Product Categories: ACTIVE PHARMACEUTICAL INGREDIENTS;Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;API;Prevention and control of e. coli
• Mol File: 965-52-6.mol
• Article Data: 5

Chemical Properties

• Melting Point: 281-283°C
• Boiling Point: 418.17°C (rough estimate)
• Appearance: Yellow solid
• Density: 1.3877 (rough estimate)
• Refractive Index: 1.5700 (estimate)
• Storage Temp.: Refrigerator, Under Inert Atmosphere
• Solubility: Practically insoluble in water, slightly soluble in ethanol (96 per cent), practically insoluble in methylene chloride.
• PKA: 8.36±0.15(Predicted)
• BRN: 4264976
• CAS DataBase Reference: Nifuroxazide(CAS DataBase Reference)
• NIST Chemistry Reference: Nifuroxazide(965-52-6)
• EPA Substance Registry System: Nifuroxazide(965-52-6)

Safety Data

• WGK Germany: 3
• RTECS: DH2528300
• Hazardous Substances Data: 965-52-6(Hazardous Substances Data)

Usage

Chemical Properties

Yellow Solid

Originator

Ercefuryl,Carriere,France,1964

Uses

Nifuroxazide is an intestinal antiseptic. Nifuroxazide, is still used as a veterinary drug illegally in some countries. SEE H829102 as a test for antibiotic in broiler chickens.

Definition

Nifuroxazide is a member of benzoic acids. Nifuroxazide is an oral nitrofuran antibiotic used to treat mild diarrhea in humans and animals.

Manufacturing Process

13 g (0.1 mol) of 4-hydroxybenzhydrazide were dissolved in a boiling mixture of 100 ml of water and an equal volume of dimethylformamide. 15.5 g (0.11 mol) of 5-nitrofurfural dissolved in 31 ml of dimethylformamide were added to this hot solution, and the mixture was stirred and brought to the boiling point.The mixture was then allowed to stand for fifteen hours. The precipitate was separated, washed twice with 100 ml of water, and recrystallized by dissolving it in 250 ml of hot pyridine and pouring this solution into 250 ml of water.The 5-nitrofurfurylidene hydrazide of 4-hydroxybenzoic acid obtained was washed with water and methanol and was dried at a moderate temperature. It weighed 23 g (83.7% yield), and melted at 298°C. The percentage nitrogen determined by the micro-Dumas method was 15.41% (theory 15.27%).

Biological Activity

Nifuroxazide is a nitrofuran antibiotic. It is active against strains of the enteropathogenic bacteria C. jejuni, Salmonella, Y. enterocolitica, Shigella, and E. coli. It inhibits quorum sensing and virulence factor production in P. aeruginosa. Nifuroxazide inhibits STAT3 activity in a reporter assay (IC50 = ~3 μM) and decreases viability of U266 and INA-6 myeloma cells, which have constitutive STAT3 phosphorylation, with EC50 values of approximately 4.5 μM for both. It also decreases viability, migration, and invasion of, and induces apoptosis in, MCF-7, 4T1, and MDA-MB-231 breast cancer cells. Nifuroxazide (50 mg/kg per day) reduces tumor growth and prevents pulmonary metastasis in a 4T1 murine mammary carcinoma model. It also reduces diarrhea, weight loss, and colon inflammation in a rat model of acetic acid-induced ulcerative colitis.

InChI:InChI=1/C12H9N3O5/c16-9-3-1-8(2-4-9)12(17)14-13-7-10-5-6-11(20-10)15(18)19/h1-7,16H,(H,14,17)/b13-7+

Synthetic route

5-nitrofurane-2-carboxaldehyde (698-63-5) + 4-hydroxybenzoic acid hydrazide (5351-23-5) → nifuroxazide (965-52-6)

Conditions	Yield
In ethanol; water Heating;	80%
Stage #1: 4-hydroxybenzoic acid hydrazide With acetic acid In water for 0.0833333h; Sonication; Stage #2: 5-nitrofurane-2-carboxaldehyde In dimethyl sulfoxide at 20℃; for 0.5h; Sonication;	65%

nifuroxazide (965-52-6) → 4-Hydroxy-benzoic acid [4-cyano-2-oxo-but-(E)-ylidene]-hydrazide (133368-17-9) + 4-Hydroxy-benzoic acid [1-(5-amino-furan-2-yl)-meth-(E)-ylidene]-hydrazide (133368-14-6)

Conditions	Yield
In methanol; water at 30℃; electrolysis;	A 5% B 35%
In 2-methoxy-ethanol; water at 30℃; electrolysis;	A 25% B n/a

Upstream product

• 92-55-7 5-nitro-2-furfuraldehyde diacetate 
• 5351-23-5 4-hydroxybenzoic acid hydrazide 
• 698-63-5 5-nitrofurane-2-carboxaldehyde 
• 28141-24-4 4-hydroxybenzoyl chloride 
• 99-96-7 4-hydroxy-benzoic acid 
• 99-76-3 methyl 4-hydroxylbenzoate 

Downstream Products

• 133368-17-9 4-Hydroxy-benzoic acid [4-cyano-2-oxo-but-(E)-ylidene]-hydrazide 
• 133368-14-6 4-Hydroxy-benzoic acid [1-(5-amino-furan-2-yl)-meth-(E)-ylidene]-hydrazide 

Relevant articles and documents

Nitrofuran drugs beyond redox cycling: Evidence of Nitroreduction-independent cytotoxicity mechanism

Nitrofurans (5-nitro-2-hydrazonylfuran as pharmacophore) are a group of widely used antimicrobial drugs but also associated to a variety of side effects. The molecular mechanisms that underlie the cytotoxic effects of nitrofuran drugs are not yet clearly understood. One-electron reduction of 5-nitro group by host enzymes and ROS production via redox cycling have been attributed as mechanisms of cell toxicity. However, the current evidence suggests that nitrofuran ROS generation by itself is uncapable to explain the whole toxic effects associated to nitrofuran consumption, proposing a nitro-reduction independent mechanism of toxicity. In the present work, a series of nitrated and non-nitrated derivatives of nitrofuran drugs were synthesized and evaluated in vitro for their cytotoxicity, ROS-producing capacity, effect on GSH-S-transferase and antibacterial activity. Our studies showed that in human cells non-nitrated derivatives were less toxic than parental drugs but, unexpectedly preserved the ability to generate intracellular ROS in similar amounts to nitrofurans despite not entering into a redox cycle mechanism. In addition, some non-nitrated derivatives although being uncapable to generate ROS exhibited the highest cell toxicity among all derivatives. Inhibition of cytosolic glutathione-S-transferase activity by some derivatives was also observed. Finally, only nitrofuran derivatives displayed antibacterial effect. Results suggest that the combined 2-hydrazonylfuran moiety, redox cycling of 5-nitrofuran, and inhibitory effects on antioxidant enzymes, would be finally responsible for the toxic effects of the studied nitrofurans on mammalian cells.

Synthesis and investigation of antimicrobial activity of some nifuroxazide analogues

A series of nifuroxazide analogues [(2a-2e)-(10a-10f)] have been synthesized, structurally identified and tested for antimicrobial activity against a panel of bacteria (Gram-positive and Gram-negative) and the yeast-like pathogenic fungus Candida albicans. The most active compound in this series was 4-amino-benzoic acid (5-nitro-furan-2-ylmethylene)-hydrazide (2b) and 2-amino-benzoic acid (5-nitrofuran-2-ylmethylene)-hydrazide (2d). Furthermore, compounds (9a-9g) and (10a-10g) recorded no activity against selected species except compounds (9f) and (10f) suggesting that using furoic hydrazide and the corresponding hydrazide of thiophene did not improve the antimicrobial activities for this type of compounds. Regarding the activity against Candida albicans, all compounds showed no activity with an exception of substituted nitro furan (2a-2d).

Synthesis and biological activity of nifuroxazide and analogs

Nifuroxazide and thirteen analogs were synthesized from substituted benzoic acids and minimal inhibitory concentrations were determined using the serial dilution tests, in three sequential steps. Nifuroxazide and chloramphenicol were used as reference standards. The tests were performed in TSB against the standard bacterial strain of Staphylococcus aureus ATCC 25923.