50-65-7

Usage

Uses

Used in Pharmaceutical Industry:
Niclosamide is used as an anthelmintic agent for the treatment of tapeworm infections caused by various species such as Taenia saginata, Taenia solium, Diphyllobothrium latum, Fasciolopsis buski, and Hymenolepis nana. It is an effective alternative to praziquantel for treating infections caused by T. saginata (beef tapeworm), T. solium (pork tapeworm), and D. latum (fish tapeworm) and is active against most other tapeworm infections. A single dose is usually adequate to produce a cure rate of 95%. However, with the availability of other agents, Niclosamide is no longer widely used.
Used in Research Applications:
Niclosamide is used in the study of the Wnt/Frizzled-1 signaling pathway, as it has been demonstrated to induce Wnt-independent Frizzled1 and Dishevelled-2 downregulation. This makes it a valuable tool for understanding the mechanisms underlying this pathway and its role in various biological processes.
Used in Cancer Research and Treatment:
Niclosamide is used as an inhibitor of the Stat3 signaling pathway, which plays a crucial role in the development and progression of various cancers. It has been shown to efficiently inhibit breast cancer stem-like cells in vitro and in vivo. Additionally, Niclosamide is used to inhibit transcription and DNA binding of the NF-κB pathway and increases reactive oxygen species (ROS) levels to induce apoptosis in acute myelogenous leukemia (AML) cells.
Used in Drug Delivery Systems:
Although not explicitly mentioned in the provided materials, Niclosamide's properties as an inhibitor of mTORC1 signaling and its ability to stimulate autophagy make it a potential candidate for development in drug delivery systems. These systems could be designed to enhance the delivery, bioavailability, and therapeutic outcomes of Niclosamide in various applications, including cancer treatment and other conditions where the inhibition of specific signaling pathways is desired.

Anti-parasitic disease drug

Niclosamide belongs to the taeniafuge drugs of the anti-parasitic disease drugs , it is less toxic, it has a high efficacy on a variety of tapeworm, tapeworm mechanism is hampering tapeworm Krebs cycle, so that lactic acid is accumulated which can cause the death of the parasites, it is drug of choice in livestock and poultry, pet tapeworm prevention . Oral absorption from the gastrointestinal tract is very little, so it can maintain a high concentration in the intestine, it has a strong insecticidal action against the pork tapeworm, and beef tapeworm short Hymenolepis . Low concentrations of the drug can promote parasite uptake, while high concentrations of the drug can inhibit mitochondrial oxidative phosphorylation of the parasite, and hinder the absorption of glucose uptake,and result in tapeworm head and proximal segments death, and elimination with the feces from the intestinal wall . Mainly it is used for tapeworm infection, but it is also used as molluscidal drugs which can kill snails and snail eggs, cercariae and miracidia. It has high rate of snail eradication , slow effect, long residual effect, it is used for the prevention of schistosomiasis, the temperature above 20 ℃ is better. In addition ,the product is friendly to human, animal and plant,it is very toxic to fish, so use in the fish ponds is forbidden . 1960 Germany reported a synthetic chemical repellent-Niclosamide whose code is Bayer 73 the drug is pale yellow powder, odorless, tasteless. Insoluble in water, slightly soluble in alcohol, ether and chloroform,it can be dissolved in hot ethanol, cyclohexanone and an aqueous solution of sodium hydroxide, the compound is stable.Niclosamide have a better effect on beef tapeworm, pork tapeworm, H. nana and Diphyllobothrium tapeworm, . Few drug absorption occurs in the gastrointestinal tract, when the drug is exposed with parasites, parasites die soon. Therefore, when the medication, the tablets should be chewed, so drugs can make full contact with tapeworm parasites, and a lot of water immediately should be avoided, in order to maintain a high concentration of upper small intestine where lies the parasitic tapeworm . The drug can kill adults tapeworm rather than eggs tapeworm , in order to prevent vomiting, which make the eggs reflux into stomach , and cause the risk of cysticercosis occurring, anti-emetics should be added before the medication . 2 hours after administration, it should be served magnesium sulfate for catharsis, to get rid of the parasite and the cleaved head section and debris. The drug has low toxicity, rat oral LD50 of 5g/kg. This product can also be made with amino ethanol to serve as soluble snail drugs under the trade name niclosamide (bayluscide),in the country, Niclosamide and alkali waste pulp can be made for soluble pastes, called schistosomiasis-67. These can be used to kill the snail which is the intermediate host of Schistosoma japonicum. Regardless of spraying or soaking ,the amount of snail, is 1g/m2. Pulp paste for live use (ie schistosomiasis-67), accounts for 50% of Niclosamide . Oral adverse reactions are mild, except for gastrointestinal reactions, occasional dizziness, chest tightness, fever and other discomfort occur. There is no liver, kidney, blood system injury. The above information is edited by the lookchem of Tian Ye.

Pharmacology and mechanism of action

Niclosamide is a chlorinated salicylanilide derivative which was introduced during the 1960s. It is an anthelminthic drug highly effective against beef tapeworm (Taenia (T.) saginata), pork tapeworm (T. solium), fish tapeworm (Diphyllobothrium (D.) latum) and dwarf tapeworm (Hymenolepis (H.) nana). The mechanism of action of the drug is not clearly known. It interferes with the energy metabolism of helminths, possibly by inhibiting adenosine triphosphate (ATP) production. It also inhibits glucose uptake by the parasites [1].

Indications

Infections caused by T. saginata, D. latum, and H. nana. The drug is also effective against T. solium, but the danger of cysticercosis makes praziquantel preferable.

Side effects

Niclosamide is generally free of undesirable effects. Minor gastrointestinal complaints such as nausea, vomiting, abdominal pain, diarrhoea, light-headedness and pruritus are rarely encountered.

Side effects

No serious side effects are associated with niclosamide use, although some patients report abdominal discomfort and loose stools.

Side effects

Very few side effects have been reported, but these include mild nausea, abdominal cramps and dizziness.

Contraindications and precautions

Drugs which cause vomiting should not be taken simultaneously with niclosamide to avoid retrograde infection by eggs. Use of niclosamide against T. solium infection may expose the patient to the risk of cysticercosis. In such a case, special precautions are needed (see Dosage below).

Preparations

? Niclocide? (Miles). Tablets 500 mg. ? Trédémine? (Bellon). Tablets 500 mg. ? Yomesan? (Bayer). Tablets 500 mg.

Acute toxicity

Oral-rat LD50: 2500 mg/kg; Oral-Mouse LD50: 1000 mg/kg

Flammability and hazard characteristics

It produces toxic chloride and nitrogen oxide gases from combustion.

Storage Characteristics

Ventilated, low-temperature ,dry storeroom.It should be stored and transported separately From food raw materials

Extinguishing agent

Dry powder , foam, sand

References

1. Webster LT Jr (1990). Drugs used in the chemotherapy of helminthiasis. In: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 8th edn, edited by A.G.Gilman, T.W.Rall, A.S.Nies, P.Taylor, (New York: Pergamon Press), pp. 965–966.

References

1) Balgi et al. (2009), Screen for chemical modulators of autophagy reveals novel therapeutic inhibitors of mTORC1 signaling; PloS One, 4 e7124 2) Ren et al. (2010), Identification of Niclosamide as a New Small-Molecule Inhibitor of the STAT3 Signaling Pathway; ACS Med. Chem. Lett., 1 454

Originator

Yomesan,Bayer,W. Germany,1960

Manufacturing Process

17.2 g of 5-chlorosalicylic acid and 20.8 g of 2-chloro-4-nitroaniline are dissolved in 250 ml of xylene. While boiling, there are introduced slowly 5 g of PCl3.Heating is continued for 3 further hours. The mixture is then allowed to cool down and the crystals which separate are filtered off with suction. The crude product may be recrystallized from ethanol, melting at 233°C.

Therapeutic Function

Anthelmintic

Antimicrobial activity

Useful activity is restricted to intestinal tapeworms, including Taeniarhynchus saginatus (syn. Taenia saginata), Taenia solium, Diphyllobothrium latum and Hymenolepis nana. It is not effective against larval stages of tapeworms.

Pharmaceutical Applications

A synthetic chlorinated nitrosalicylanilide available for oral administration.

Biochem/physiol Actions

Niclosamide uncouples oxidative phosphorylation in the tapeworm and inhibits mitochondrial oxidative phosphorylation of parasitic helminths. It blocks tumor necrosis factor-induced IκBα phosphorylation, translocation of p65, and expression of NF-κΒ– regulated genes in AML cells.

Mechanism of action

For many years, niclosamide (Niclocide) was widely used to treat infestations of cestodes. Niclosamide is a chlorinated salicylamide that inhibits the production of energy derived from anaerobic metabolism. It may also have adenosine triphosphatase (ATPase) stimulating properties. Inhibition of anaerobic incorporation of inorganic phosphate into ATP is detrimental to the parasite. Niclosamide can uncouple oxidative phosphorylation in mammalian mitochondria, but this action requires dosages that are higher than those commonly used in treating worm infections. The drug affects the scolex and proximal segments of the cestodes, resulting in detachment of the scolex from the intestinal wall and eventual evacuation of the cestodes from the intestine by the normal peristaltic action of the host's bowel. Because niclosamide is not absorbed from the intestinal tract, high concentrations can be achieved in the intestinal lumen.The drug is not ovicidal.

Pharmacokinetics

Conflicting data exist relative to the level of absorption of niclosamide from the gut. The metabolized drug is passed in the feces and urine, staining them yellow.

Clinical Use

5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamideor 2,5 -dichloro-4 -nitrosalicylanilide (Cestocide, Mansonil,Yomesan) occurs as a yellowish white, water-insolublepowder. It is a potent taeniacide that causes rapid disintegrationof worm segments and the scolex. Penetration of thedrug into various cestodes appears to be facilitated by thedigestive juices of the host, in that very little of the drug isabsorbed by the worms in vitro. Niclosamide is well toleratedfollowing oral administration, and little or no systemicabsorption of it occurs. A saline purge 1 to 2 hours after ingestion of the taeniacide is recommended to remove thedamaged scolex and worm segments. This procedure ismandatory in the treatment of pork tapeworm infestation toprevent possible cysticercosis resulting from release of liveova from worm segments damaged by the drug.

Clinical Use

Niclosamide has been used extensively in the treatment of tapeworm infections caused by Taenia saginata, Taenia solium, Diphyllobothrium latum, Fasciolopsis buski, and Hymenolepis nana. It is an effective alternative to praziquantel for treating infections caused by T. saginata (beef tapeworm), T. solium (pork tapeworm), and D. latum (fish tapeworm) and is active against most other tapeworm infections. It is absorbed by intestinal cestodes but not nematodes.A single dose is usually adequate to produce a cure rate of 95%.With H. nana (dwarf tapeworm), a longer treatment course (up to 7 days) is necessary. Niclosamide is administered orally after the patient has fasted overnight and may be followed in 2 hours by purging (magnesium sulfate 15–30 g) to encourage complete expulsion of the cestode, especially T. solium, although this is not always considered necessary. Cure is assessed by follow-up stool examination in 3 to 5 months.With the availability of other agents, niclosamide is no longer widely used.The most widely employed agents are praziquantel and the benzimidazoles.

Safety Profile

Poison by intravenous and intraperitoneal routes. Moderately toxic by ingestion. Experimental reproductive effects. Human mutation data reported. When heated to decomposition it emits very toxic fumes of Cl and NOx.

Synthesis

Niclosamide, 2
,5-dichloro-4
nitrosaicylanilide (38.1.34), is made by reacting 5-chlorosalicylic acid with 2-chloro-4-nitroaniline in the presence of phosphorus trichloride.

InChI:InChI=1/C13H8Cl2N2O4/c14-7-1-4-12(18)9(5-7)13(19)16-11-6-8(17(20)21)2-3-10(11)15/h1-6,18H,(H,16,19)

Synthetic route

5-chloro-2-hydroxybenzoic acid (321-14-2) + 2-Chloro-4-nitroaniline (121-87-9) → Niclosamide (50-65-7)

Conditions	Yield
With phosphorus trichloride In chlorobenzene at 135℃; for 3h; Concentration; Solvent;	68.7%
With thionyl chloride In 5,5-dimethyl-1,3-cyclohexadiene at 78℃; for 6.1h; Temperature; Reflux;
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;
With phosphorus trichloride In 5,5-dimethyl-1,3-cyclohexadiene for 4h; Reflux;

5-chloro-N-(2-chlorophenyl)-2-hydroxybenzamide (6626-92-2) → Niclosamide (50-65-7)

Conditions	Yield
With 3-(ethoxycarbonyl)-1-(5-methyl-5-(nitrosooxy)hexyl)pyridin-1-ium bis(trifluoromethanesulfonyl)imide at 20℃; for 5h; Ionic liquid;	48%

niclosamide-2-O-glucuronide → Niclosamide (50-65-7)

Conditions	Yield
With β-glucuronidase for 0.333333h;

5-chloro-2-hydroxybenzoyl chloride (15216-81-6) + 2-Chloro-4-nitroaniline (121-87-9) → Niclosamide (50-65-7)

Conditions	Yield
With dmap; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; dichloromethane
In dichloromethane at 25℃; Inert atmosphere;

5-chloro-2-hydroxybenzoic acid (321-14-2) → Niclosamide (50-65-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: thionyl chloride; N,N-dimethyl-formamide / dichloromethane / 12 h / 25 °C 2: dichloromethane / 25 °C / Inert atmosphere View Scheme

Niclosamide (50-65-7) + N,N-Dimethylcarbamoyl chloride (79-44-7) → 4-chloro-2-((2-chloro-4-nitrophenyl)carbamoyl)phenyl dimethylcarbamate (1187819-29-9)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran Reflux;	100%
With pyridine; dmap Reflux;

Niclosamide (50-65-7) → N-(4-amino-2-chloro-phenyl)-5-chloro-2-hydroxy-benzamide

Conditions	Yield
With ammonium chloride; zinc In methanol at 0 - 20℃; for 16h;	100%
With ammonium chloride; zinc In methanol; water at 0 - 20℃; for 16h; Inert atmosphere;	100%
With palladium 10% on activated carbon; hydrogen In methanol; ethyl acetate at 20℃; under 3000.3 Torr; for 3h;	99.9%

Niclosamide (50-65-7) + phosphonic acid diethyl ester (762-04-9) → 4-chloro-2-((2-chloro-4-nitrophenyl)carbamoyl)phenyl diethyl phosphate

Conditions	Yield
With dmap; N-ethyl-N,N-diisopropylamine In tetrachloromethane; N,N-dimethyl-formamide at 0℃; for 2h;	96.2%

morpholine (110-91-8) + formaldehyd (50-00-0) + Niclosamide (50-65-7) → 5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxy-3-(morpholinomethyl)benzamide (860032-69-5)

Conditions	Yield
In ethanol; water for 2h; Mannich reaction; Heating;	95%
In ethanol; water Mannich reaction; Reflux;	95%

Niclosamide (50-65-7) + methyl iodide (74-88-4) → 5-chloro-N-(2-chloro-4-nitrophenyl)-2-methoxybenzamide (32060-31-4)

Conditions	Yield
With potassium carbonate In acetone for 15h; Reflux; Sealed tube; Inert atmosphere;	94%

Niclosamide (50-65-7) + 2-(2-tert-butyloxycarbonylaminoethoxy)ethanol (139115-91-6) → (2-{2-[4-chloro-2-(2-chloro-4-nitro-phenylcarbamoyl)-phenoxy]-ethoxy}-ethyl)carbamic acid tert-butyl ester

Conditions	Yield
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 2h;	93%
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 2h; Mitsunobu Displacement; Inert atmosphere;

formaldehyd (50-00-0) + Niclosamide (50-65-7) + dimethyl amine (124-40-3) → 5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxy-3-(dimethylaminomethyl)benzamide

Conditions	Yield
In ethanol; water for 2h; Mannich reaction; Heating;	92%

Niclosamide (50-65-7) + tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (77279-24-4) → 4-{2-[4-chloro-2-(2-chloro-4-nitro-phenylcarbamoyl)-phenoxy]-ethyl}-piperazine-1-carboxylic acid tert-butyl ester (1420290-97-6)

Conditions	Yield
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 2h;	91%
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 2h; Mitsunobu Displacement; Inert atmosphere;

formaldehyd (50-00-0) + Niclosamide (50-65-7) + diethylamine (109-89-7) → 5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxy-3-(diethylaminomethyl)benzamide

Conditions	Yield
In ethanol; water for 2h; Mannich reaction; Heating;	90%

Niclosamide (50-65-7) + acetic anhydride (108-24-7) → 4-chloro-2-((2-chloro-4-nitrophenyl)carbamoyl)phenyl acetate

Conditions	Yield
With dmap In N,N-dimethyl-formamide at 0℃;	88.2%
With phosphoric acid at 70℃; for 1h;	83%
With dmap In dichloromethane at 20℃; for 18h;

piperidine (110-89-4) + formaldehyd (50-00-0) + Niclosamide (50-65-7) → 5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxy-3-(piperidinomethyl)benzamide (164589-62-2)

Conditions	Yield
In ethanol; water for 2h; Mannich reaction; Heating;	87%
In ethanol; water Mannich reaction; Reflux;	87%

2-fluoroethanol (371-62-0) + Niclosamide (50-65-7) → 5-chloro-N-(2-chloro-4-nitro-phenyl)-2-(2-fluoro-ethoxy)benzamide (1420290-80-7)

Conditions	Yield
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 16h; Mitsunobu Displacement; Inert atmosphere;	86%

acetoxymethyl bromide (590-97-6) + Niclosamide (50-65-7) → acetic acid 4-chloro-2-(2-chloro-4-nitrophenylcarbamoyl)phenoxymethyl ester

Conditions	Yield
With potassium carbonate In acetonitrile at 20℃;	86%

n-Dodecylamine (124-22-1) + Niclosamide (50-65-7) → dodecan-1-aminium 4-chloro-2-[(2-chloro-4-nitrophenyl)carbamoyl]phenoxide (1619232-16-4)

Conditions	Yield
In ethanol at 20℃; for 336h;	84%

2,5-Dihydro-2,5-dioxo-1H-pyrrole-1-hexanoic acid (55750-53-3) + Niclosamide (50-65-7) → (4-chloro-2-((2-chloro-4-nitrophenyl)carbamoyl)phenyl-6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoate)

Conditions	Yield
With triethylamine; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃; for 0.25h; Inert atmosphere;	82%

4-morpholinocarbonyl chloride (15159-40-7) + Niclosamide (50-65-7) → 4-chloro-2-((2-chloro-4-nitrophenyl)carbamoyl)phenyl morpholine-4-carboxylate (1243092-32-1)

Conditions	Yield
With pyridine at 60℃;	81%
With pyridine; dmap for 3h; Reflux;

hexadecylamine (143-27-1) + Niclosamide (50-65-7) → hexadecan-1-aminium 4-chloro-2-[(2-chloro-4-nitrophenyl)carbamoyl]phenoxide (1619232-17-5)

Conditions	Yield
In ethanol at 20℃; for 336h;	81%

Niclosamide (50-65-7) → 5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzenecarbothioamide (23238-76-8)

Conditions	Yield
With Lawessons reagent In acetonitrile for 24h; Reflux;	80%

Niclosamide (50-65-7) + 8-tosyloxy-3,6-dioxaoctanol (77544-68-4) → O-(2-[2-(2-hydroxyethoxy)ethoxy]ethyl)niclosamide (1046321-41-8)

Conditions	Yield
With tetrabutylammomium bromide; potassium carbonate In 1,4-dioxane at 79.99℃; for 12h;	79%
With tetrabutylammomium bromide; potassium carbonate In 1,4-dioxane at 85℃; for 6h; Reflux;	78%

isocyanate de chlorosulfonyle (1189-71-5) + Niclosamide (50-65-7) → 4-chloro-2-((2-chloro-4-nitrophenyl)carbamoyl)phenyl sulfamate

Conditions	Yield
Stage #1: isocyanate de chlorosulfonyle With formic acid at 0℃; Stage #2: Niclosamide With pyridine In dichloromethane at 50℃; for 6h;	76%

Niclosamide (50-65-7) + n-hexadecanoyl chloride (112-67-4) → 4-chloro-2-(2-chloro-4-nitroanilinocarbonyl)phenyl hexadecanoate

Conditions	Yield
With pyridine In chloroform at 0℃; for 3h;	75%

Niclosamide (50-65-7) + 2-bromoethanol (540-51-2) → 2-(2-bromoethoxy)-5-chloro-N-(2-chloro-4-nitrophenyl)benzamide (1046321-35-0)

Conditions	Yield
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 16h; Mitsunobu Displacement; Inert atmosphere;	75%

aminoethylpiperazine (140-31-8) + Niclosamide (50-65-7) → 4-(2-ammonioethyl)piperazin-1-ium bis-{4-chloro-2-[(2-chloro-4-nitrophenyl)carbamoyl]phenoxide}

Conditions	Yield
In ethanol at 20℃; for 337.92h;	74%

2-(N-tert-butoxycarbonylamino)ethanol (26690-80-2) + Niclosamide (50-65-7) → {2-[4-chloro-2-(2-chloro-4-nitro-phenylcarbamoyl)-phenoxy]-ethyl}-carbamic acid tert-butyl ester

Conditions	Yield
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃;	71%
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran	45%
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 2h; Mitsunobu Displacement; Inert atmosphere;

Niclosamide (50-65-7) + p-toluenesulfonic acid 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl ester (77544-60-6) → 2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethoxyl niclosamide

Conditions	Yield
With tetrabutylammomium bromide; potassium carbonate In 1,4-dioxane at 79.99℃; for 12h;	70%

formaldehyd (50-00-0) + Niclosamide (50-65-7) + glycine acetate (58556-46-0) → 3'-(N-glycinomethyl)-2,5'-dichloro-4-nitrosalicylanilide

Conditions	Yield
In ethanol; water 1.) reflux, 5 h, 2.) r.t., overnight;	65%

Niclosamide (50-65-7) → 6-chloro-3-(2-chloro-4-nitrophenyl)benzo[e][1,2,3]oxathiazin-4(3H)-one 2,2-dioxide

Conditions	Yield
Stage #1: Niclosamide With N-ethyl-N,N-diisopropylamine In acetonitrile Stage #2: With potassium fluoride; N,N`-sulfuryldiimidazole; trifluoroacetic acid In water at 20℃; for 18h;	64%

Niclosamide (50-65-7) → C13H6(2)H2Cl2N2O4

Conditions	Yield
With rhodium(III) chloride; water-d2 In N,N-dimethyl-formamide at 108℃;	60%

Upstream product

• 321-14-2 5-chloro-2-hydroxybenzoic acid 
• 121-87-9 2-Chloro-4-nitroaniline 
• 15216-81-6 5-chloro-2-hydroxybenzoyl chloride 
• 6626-92-2 5-chloro-N-(2-chlorophenyl)-2-hydroxybenzamide 

Downstream Products

• 164589-62-2 5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxy-3-(piperidinomethyl)benzamide 
• 860032-69-5 5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxy-3-(morpholinomethyl)benzamide 
• 50736-78-2 6-chloro-3-(2-chloro-4-nitro-phenyl)-2-trifluoromethylimino-2,3-dihydro-benzo[e][1,3]oxazin-4-one 
• 1187819-29-9 4-chloro-2-((2-chloro-4-nitrophenyl)carbamoyl)phenyl dimethylcarbamate 
• 1187819-32-4 (S)-2-tert-butyl 1-(4-chloro-2-(2-chloro-4-nitrophenylcarbamoyl)phenyl) pyrrolidine-1,2-dicarboxylate 
• 1187819-49-3 (R)-4-chloro-2-(2-chloro-4-nitrophenylcarbamoyl)phenyl 2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate 
• 1187819-31-3 (S)-1-(4-chloro-2-((2-chloro-4-nitrophenyl)carbamoyl)phenyl) 2-methyl pyrrolidine-1,2-dicarboxylate 
• 23238-76-8 5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzenecarbothioamide 
• 1401460-92-1 N-(4-amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide hydrochloride 
• 1243092-32-1 4-chloro-2-((2-chloro-4-nitrophenyl)carbamoyl)phenyl morpholine-4-carboxylate 
• 1243092-28-5 4-chloro-2-((2-chloro-4-nitrophenyl)carbamoyl)phenyl 4-methylpiperazine-1-carboxylate 
• 1420290-87-4 5-chloro-N-(2-chloro-4-nitro-phenyl)-2-(piperidin-4-yloxy)benzamide 
• 1420290-88-5 2-(2-aminoethoxy)-5-chloro-N-(2-chloro-4-nitrophenyl)benzamide 
• 1420290-89-6 2-(3-aminopropoxy)-5-chloro-N-(2-chloro-4-nitrophenyl)benzamide 

Relevant academic research and scientific papers

Metabolism of the anthelmintic drug niclosamide by cytochrome P450 enzymes and UDP-glucuronosyltransferases: Metabolite elucidation and main contributions from CYP1A2 and UGT1A1

1. Niclosamide is an old anthelmintic drug that shows potential in fighting against cancers. Here, we characterized the metabolism of niclosamide by cytochrome P450 enzymes (CYPs) and UDP-glucuronosyltransferases (UGTs) using human liver microsomes (HLM) and expressed enzymes.2. NADPH-supplemented HLM (and liver microsomes from various animal species) generated one hydroxylated metabolite (M1) from niclosamide; and UDPGA-supplemented liver microsomes generated one mono-O-glucuronide (M2). The chemical structures of M1 (3-hydroxy niclosamide) and M2 (niclosamide-2-O-glucuronide) were determined through LC-MS/MS and/or NMR analyses.3. Reaction phenotyping revealed that CYP1A2 was the main enzyme responsible for M1 formation. The important role of CYP1A2 in niclosamide metabolism was further confirmed by activity correlation analyses as well as inhibition experiments using specific inhibitors.4. Although seven UGT enzymes were able to catalyze glucuronidation of niclosamide, UGT1A1 and 1A3 were the enzymes showed the highest metabolic activities. Activity correlation analyses demonstrated that UGT1A1 played a predominant role in hepatic glucuronidation of niclosamide, whereas the role of UGT1A3 was negligible.5. In conclusion, niclosamide was subjected to efficient metabolic reactions hydroxylation and glucuronidation, wherein CYP1A2 and UGT1A1 were the main contributing enzymes, respectively.

Application of niclosamide and analogs as small molecule inhibitors of Zika virus and SARS-CoV-2 infection

Zika virus has emerged as a potential threat to human health globally. A previous drug repurposing screen identified the approved anthelminthic drug niclosamide as a small molecule inhibitor of Zika virus infection. However, as antihelminthic drugs are generally designed to have low absorption when dosed orally, the very limited bioavailability of niclosamide will likely hinder its potential direct repurposing as an antiviral medication. Here, we conducted SAR studies focusing on the anilide and salicylic acid regions of niclosamide to improve physicochemical properties such as microsomal metabolic stability, permeability and solubility. We found that the 5-bromo substitution in the salicylic acid region retains potency while providing better drug-like properties. Other modifications in the anilide region with 2′-OMe and 2′-H substitutions were also advantageous. We found that the 4′-NO2 substituent can be replaced with a 4′-CN or 4′-CF3 substituents. Together, these modifications provide a basis for optimizing the structure of niclosamide to improve systemic exposure for application of niclosamide analogs as drug lead candidates for treating Zika and other viral infections. Indeed, key analogs were also able to rescue cells from the cytopathic effect of SARS-CoV-2 infection, indicating relevance for therapeutic strategies targeting the COVID-19 pandemic.

Benzoylaniline compound and application of benzoylaniline compound in preparation of sensitizer of P.aeruginosa inhibitor

The invention discloses a benzoylaniline compound. The benzoylaniline compound has a structural general formula shown in the specification. The invention also discloses application of the benzoylaniline compound in preparation of a sensitizer of a P.aeruginosa inhibitor or in preparation of a medicine for preventing or treating bacterial infection diseases caused by P.aeruginosa. The invention also discloses an application of niclosamide in preparation of a sensitizer of a P.aeruginosa inhibitor or in preparation of a medicine for preventing or treating bacterial infection diseases caused by P.aeruginosa. The benzoylaniline compound provided by the invention can be used as a medicine for treating and/or preventing bacterial infection diseases caused by P.aeruginosa.

3-(Ethoxycarbonyl)-1-(5-methyl-5-(nitrosooxy)hexyl)pyridin-1-ium cation: A green alternative to tert-butyl nitrite for synthesis of nitro-group-containing arenes and drugs at room temperature

Due to their remarkable properties, task-specific ionic liquids have turned out to be progressively popular over the last few years in the field of green organic synthesis. Herein, for the first time, we report that a new task-specific nitrite-based ionic liquid such as 3-(ethoxycarbonyl)-1-(5-methyl-5-(nitrosooxy)hexyl)pyridin-1-ium bis(trifluoromethanesulfonyl)imides (TS-N-IL) derived from biodegradable ethyl nicotinate indeed acted as an efficient and eco-friendly reagent for the synthesis of highly valuable nitroaromatic compounds and drugs including nitroxynil, tolcapone, niclofolan, flutamide, niclosamide and nitrazepam. The bridging of an ionic liquid with nitrite group not only increases the yield and rate of direct C[sbnd]N bond formation reaction but also allows easy product separation and recyclability of a byproduct. Nonvolatile nature, easy synthesis, merely stoichiometric need and mildness are a portion of the extra focal points of TS-N-IL while contrasted with tert-butyl nitrite an outstanding and highly-flammable reagent utilized largely in organic synthesis.

SAR optimization studies on modified salicylamides as a potential treatment for acute myeloid leukemia through inhibition of the CREB pathway

Disruption of cyclic adenosine monophosphate response element binding protein (CREB) provides a potential new strategy to address acute leukemia, a disease associated with poor prognosis, and for which conventional treatment options often carry a significant risk of morbidity and mortality. We describe the structure-activity relationships (SAR) for a series of XX-650-23 derived from naphthol AS-E phosphate that disrupts binding and activation of CREB by the CREB-binding protein (CBP). Through the development of this series, we identified several salicylamides that are potent inhibitors of acute leukemia cell viability through inhibition of CREB-CBP interaction. Among them, a biphenyl salicylamide, compound 71, was identified as a potent inhibitor of CREB-CBP interaction with improved physicochemical properties relative to previously described derivatives of naphthol AS-E phosphate.

Identification and synthesis of low-molecular weight cholecystokinin B receptor (CCKBR) agonists as mediators of long-term synaptic potentiation

Recently, He et al. reported that CCKB receptors located in the neocortex of the brain when bound to their bound natural ligand, CCK peptides, enhance memory, bringing up the possibility that agonists targeting the CCKB receptor may act as therapeutic agents in diseases in which memory loss is marked as observed in dementia and Alzheimer’s. In this report, we describe the synthesis of novel low-molecular weight benzoamine CCKB receptor agonists. The compounds made in this series were determined to be mostly partial agonists, although some antagonists were identified, as well, capable of triggering calcium release in a cell line that overexpresses the CCKB receptor. Compound 35 demonstrated an EC50 of 0.15 μM in the cell-based assay, but more importantly, several of the compounds, including 35, demonstrated a physiological effect, inducing long-term potentiation in rat brains comparable to the CCK-8 peptide albeit at much higher concentrations. Based on these findings, benzoamines may be the basis for a new series of CCKB receptor agonists in drug-discovery efforts that seek to develop therapeutics to prevent memory loss.

Preparation method for niclosamide intermediate

The invention discloses a preparation method for a niclosamide intermediate, and the method belongs to the field of fine chemical production. In the method, the weight ratio of raw materials, for a first reaction, such as o-chloro-p-nitroaniline to xylene to thionyl chloride is (14-15.5%):(14-15.5%):(59.5%):(11%), ethanol is adopted for a second reaction, and the amount of ethanol is equal to the weight of xylene used in the first reaction. The production method has the advantages of simple process, high efficiency, low cost, no pollution, and high yield; compared with a conventional method, the production method has the advantage of low reaction temperature; with the low reaction temperature, firstly, energy is saved, and secondly, the production difficulty of a reactor is reduced; the production method has the other advantage that the yield of the product niclosamide can be increased to more than or equal to 80%, the purity of the product can reach 95.0%, and the product is mainly used for production of niclosamide.

Thioctic acid phenol ester derivative as well as preparation method and application thereof

The invention provides a thioctic acid phenol ester derivative as well as a preparation method and application thereof. The thioctic acid phenol ester derivative has a general molecular formula with a formula (I), the formula (I) is shown in the description, wherein X is halogen and R is substituted phenyl. The thioctic acid phenol ester derivative provided by the invention has a novel structure and relatively high bioactivity and has a relatively good inhibition effect on proliferation and migration of tumor cells; compared with an inhibition effect of cis-platinum on the tumor cells, the inhibition effect of the carbamoyl substituted thioctic acid phenol ester derivative provided by the invention on tumors is better than inhibition strength of the cis-platinum on the tumor cells.

INHIBITORS OF CREB-CBP INTERACTION FOR TREATMENT OF LEUKEMIA

Compounds and methods are provided for inhibiting a CREB-CBP protein-protein interaction in a sample. In some cases, the method includes modulating transcription of CREB in a cell that overexpresses CREB. Also provided are methods of inhibiting the proliferation of a cancer cell. The subject CREB transcription inhibitor compounds include a substituted salicylamide or a prodrug thereof. Methods of alleviating symptoms associated with cancer (e.g., Acute Myeloid Leukemia (AML) or Acute Lymphomblastic Leukemia (ALL)) in a subject in need thereof are also provided. Pharmaceutical compositions including the subject compounds find use in treating cancer. The subject compounds may be formulated or provided to a subject in combination with a second agent, e.g. an anticancer agent.

Niclosamide is a Negative Allosteric Modulator of Group I Metabotropic Glutamate Receptors: Implications for Neuropathic Pain

Purpose: Novel therapeutics are greatly needed that target specific pathological receptors and pathways involved in Neuropathic Pain (NP). Extending our previous work published in this Journal on Group I metabotropic glutamate receptor (mGluR) modulators, we now investigate the therapeutic potential of niclosamide in modulating aberrant glutamate transmission in NP. Method: Calcium mobilization assays and cross-receptor selectivity experiments are conducted to characterize the pharmacological activity of niclosamide. A focused series of niclosamide analogues is then prepared to elucidate key structural determinants that emerged from computational molecular modeling analysis on drug-receptor interactions. Finally, niclosamide and a carbamate derivative are studied to assess their efficacy in an NP-evoked mechanical hyperalgesia model in rats. Results: Niclosamide is a low-nanomolar allosteric antagonist of Group I mGluRs with high selectivity for Group I over homologous Group III mGluRs. The phenolic hydroxyl group of niclosamide forms a crucial hydrogen bond with mGluR1/5. Its bioactive coplanar conformation is further stabilized by the nitro substituent on the B ring and an intramolecular bond. Mechanical hyperalgesia in NP rats is reversed by niclosamide through three different dosing routes. Conclusion: To our knowledge, this is the first report of the salicylanilide class of compounds as potential treatments for NP.