Description
Niclosamide (50-65-7) reversibly inhibits mTORC1 signaling and stimulates autophagy.1 Inhibits activation and nuclear translocation of STAT3 selectively over STAT1 and STAT5. Niclosamide inhibits transcription of STAT3 target genes and induces cell cycle arrest and apoptosis in cells with constitutively active STAT3.2
Chemical Properties
Yellowish-white or yellowish, fine crystals.Yellow-white crystalline powder, odorless, tasteless. Melting point 225-230 ℃. Insoluble in water, soluble in hot ethanol, chloroform, cyclohexanone, diethyl ether and sodium hydroxide solution.
Originator
Yomesan,Bayer,W. Germany,1960
Definition
ChEBI: Niclosamide is a secondary carboxamide resulting from the formal condensation of the carboxy group of 5-chlorosalicylic acid with the amino group of 2-chloro-4-nitroaniline. It is an oral anthelmintic drug approved for use against tapeworm infections. It has a role as a piscicide, a molluscicide, an antiparasitic agent, an anticoronaviral agent, an anthelminthic drug, an apoptosis inducer and a STAT3 inhibitor. It is a member of monochlorobenzenes, a member of salicylanilides, a C-nitro compound, a secondary carboxamide and a member of benzamides. It is functionally related to a 5-chlorosalicylic acid.
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.
Brand name
Niclocide (Bayer).
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.
General Description
A cell-permeable salicylanilide that, in addition to its well-known antihelmintic efficacy, acts as a mammalian mTORC1, but not mTORC2, signaling inhibitor mechanistically distinct from rapamycin. Likely a direct consequence of autophagy activation, Niclosamide is demonstrated to induce Wnt-independent Frizzled1 and Dishevelled-2 downregulation. Unrelated to its autophagy induction activity, Niclosamide is also shown to inhibit Stat3 signaling (IC50 = 0.25 M in HeLa reporter assays). Efficiently inhibits breast cancer stem-like cells in vitro and in vivo.
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.
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
Intestinal tapeworm infections
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.
Synthesis
Niclosamide, 2,5-dichloro-4nitrosaicylanilide (38.1.34), is made by reacting 5-chlorosalicylic acid with 2-chloro-4-nitroaniline in the presence of phosphorus trichloride.
