Mebendazole

Absorption

Poorly absorbed (approximately 5 to 10%) from gastrointestinal tract. Fatty food increases absorption.

Toxicity

Acute oral toxicity (LD50): 620 mg/kg [Mouse]. Symptoms of overdose include elevated liver enzymes, headaches, hair loss, low levels of white blood cells (neutropenia), fever, and itching.

Description

Mebendazole is a broad-spectrum anthelmintic that is active against both larval and adult stages of nematodes selectively binding the β-subunit of tubulin, thereby inhibiting intestinal microtubule synthesis in the parasite (IC₅₀ = 0.19 μM for Giardia in vitro). As a tubulin-binding agent, mebendazole also possesses antitumor properties, inducing apoptosis of various human carcinomas both in vitro and in vivo, thus preventing their growth and migration. Furthermore, mebendazole has been used to inhibit hedgehog signaling in cancer cells via suppression of the formation of the primary cilium, a microtubule-based organelle that functions as a signaling hub for hedgehog pathway activation. Additionally, mebendazole has been shown to stabilize the transcriptional activator HIF-1α and its downstream targets, abrogating oxidative neuronal death in primary neurons.

Chemical properties

White Amorphous Powder

Originator

Vermox,Ortho,US ,1975

The Uses of Mebendazole

Mebendazole Polymorph C is an Anthelmintic (Nematodes).

The Uses of Mebendazole

For the treatment of Enterobius vermicularis (pinworm), Trichuris trichiura (whipworm), Ascaris lumbricoides (common roundworm), Ancylostoma duodenale (common hookworm), Necator americanus (American hookworm) in single or mixed infections.

Indications

For the treatment of Enterobius vermicularis (pinworm), Trichuris trichiura (whipworm), Ascaris lumbricoides (common roundworm), Ancylostoma duodenale (common hookworm), Necator americanus (American hookworm) in single or mixed infections.

Background

A benzimidazole that acts by interfering with carbohydrate metabolism and inhibiting polymerization of microtubules. [PubChem]

What are the applications of Application

Mebendazole is an antihelmintic small molecule compound

Definition

ChEBI: A carbamate ester that is methyl 1H-benzimidazol-2-ylcarbamate substituted by a benzoyl group at position 5.

Indications

Unlike thiabendazole, mebendazole (Vermox) does not inhibit fumarate reductase.While mebendazole binds to both mammalian and nematode tubulin, it exhibits a differential affinity for the latter, possibly explaining the selective action of the drug. The selective binding to nematode tubulin may inhibit glucose absorption, leading to glycogen consumption and ATP depletion.

Manufacturing Process

A mixture of 5.2 parts of 4-chloro-3-nitrobenzophenone, 5 parts of ammonia, 72 parts of methanol and 13 parts of sulfolane is heated overnight at 125°C in a sealed tube. The reaction mixture is evaporated in vacuo. The semisolid residue is boiled in 100 parts of a diluted hydrochloric acid solution. After cooling, the precipitated product is filtered off and dissolved in chloroform. The chloroform phase is dried and evaporated. The residue is crystallized from toluene, yielding 4-amino-3-nitrobenzophenone; MP 141°C.
A mixture of 9.6 parts of 4-amino-3-nitrobenzophenone, 160 parts of methanol, 8 parts of concentrated hydrochloric acid and 1 part of palladiumon-charcoal catalyst 10% is hydrogenated at normal pressure and at room temperature. After the calculated amount of hydrogen is taken up, hydrogenation is stopped. The catalyst is filtered off and the solvent is evaporated. The solid residue is triturated in 2-propanol. The latter is partly evaporated and the solid product is filtered off, washed with 2-propanol and dried, yielding 3,4-diaminobenzophenone hydrochloride; MP 207°C.
7.8 parts of S-methylisothiourea sulfate are stirred in 10 parts of water in an ice bath and there are added 4.5 parts of methyl chloroformate. While keeping the temperature below 20°C, there are added dropwise, in the course of 10 minutes, 17 parts of sodium hydroxide solution 25% (pH 8±), followed by the addition of 5.6 parts of acetic acid (pH 5). To this mixture is added at 20°C a suspension of 7 parts of 3,4-diaminobenzophenone hydrochloride in 100 parts of water, followed by the addition of 2.3 parts of sodium acetate.
The whole is slowly heated to 85°C and stirred at this temperature for 45 minutes. The reaction mixture is cooled and the precipitated product is filtered off. It is washed successively with water and ethanol, dried and crystallized from a mixture of acetic acid and methanol, yielding methyl N-[5(6)-benzoyl2-benzimidazolyl]carbamate; MP 288.5°C.

brand name

Vermox (McNeil).

Therapeutic Function

Anthelmintic

General Description

White to slightly yellow powder. Pleasant taste. Practically water insoluble.

Air & Water Reactions

Insoluble in water.

Reactivity Profile

Mebendazole is a carbamate ester-amine. Amines behave as chemical bases. Carbamates are chemically similar to, but more reactive than amides. Like amides they form polymers such as polyurethane resins. Carbamates are incompatible with strong acids and bases, and especially incompatible with strong reducing agents such as hydrides. Flammable gaseous hydrogen is produced by the combination of active metals or nitrides with carbamates. Strongly oxidizing acids, peroxides, and hydroperoxides are incompatible with carbamates.

Fire Hazard

Flash point data for Mebendazole are not available; however, Mebendazole is probably combustible.

Pharmaceutical Applications

A benzimidazole carbamic acid methyl ester available for oral administration. It is insoluble in water and stable at room temperature.

Mechanism of action

Mebendazole is given orally; it is poorly soluble, and very little is absorbed from the intestinal tract. About 5 to 10%, principally the decarboxylated derivatives, is recovered in the urine; most of the orally administered drug is found in the feces within 24 hours.

Pharmacokinetics

Mebendazole is a (synthetic) broad-spectrum anthelmintic. The principal mode of action for Mebendazole is by its inhibitory effect on tubulin polymerization which results in the loss of cytoplasmic microtubules.

Pharmacokinetics

Oral absorption is poor. Plasma concentrations achieved after oral administration of 100 mg every 12 h for three consecutive days do not exceed 0.03 mg/L. All metabolites are inactive. Most of the dose, as unchanged drug or a primary metabolite, is retained in the intestinal tract and passed in the feces, with the remainder, approximately 2% of the dose, excreted in the urine.

Clinical Use

Intestinal nematode infections
Trichinosis (larval stage)

Clinical Use

Methyl 5-benzoyl-2-benzimidazolecarbamate (Vermox) isa broad-spectrum anthelmintic that is effective against variousnematode infestations, including whipworm, pinworm,roundworm, and hookworm. Mebendazole irreversiblyblocks glucose uptake in susceptible helminths, thereby depletingglycogen stored in the parasite. It apparently does notaffect glucose metabolism in the host. It also inhibits cell divisionin nematodes.
Mebendazole is poorly absorbed by the oral route.Adverse reactions are uncommon and usually consist of abdominaldiscomfort. It is teratogenic in laboratory animalsand, therefore, should not be given during pregnancy.

Clinical Use

Mebendazole is used primarily for the treatment of A. lumbricoides, T. trichiura, E. vermicularis, and hookworm infections, in which it produces high cure rates. It is an alternative agent for the treatment of trichinosis and visceral larva migrans. Owing to its broad-spectrum anthelmintic effect, mixed infections (ascariasis, hookworm infestation, or enterobiasis in association with trichuriasis) frequently respond to therapy. High doses have been used to treat hydatid disease, but albendazole is now thought to be superior.

Side Effects

Diarrhea and gastrointestinal discomfort may occur, but adverse reactions are generally mild. Woman of childbearing age should be informed of a potential risk to the fetus if treated during pregnancy, particularly during the first trimester.

Side Effects

Abdominal discomfort and diarrhea may occur when the worm load is heavy. Its use is contraindicated during pregnancy.

Safety Profile

Moderately toxic by ingestion and intraperitoneal routes. Human mutation data reported. An experimental teratogen. Experimental reproductive effects. When heated to decomposition it emits toxic fumes of NOx. See also CARBAMATES.

Synthesis

Mebendazole, methyl-[5-(benzoyl)-1H-benzoimidazol-2-yl]carbamate (38.1.5), is a derivative of benzoimidazole, which is made by reacting 3,4-diaminobenzophenone (38.1.3) with N-methoxycarbonyl-S-methylthiourea (38.1.4).

The necessary reagents are made in the following manner. Nitration of 4-chlorobenzophenone with nitric acid at a temperature lower than 5°C gives 4-chloro-3-nitrobenzophenone (38.1.1), in which the chlorine atom is replaced with an amino group by heating it to 125°C in a solution of ammonia in methanol to make 4-amino-3-nitrobenzophenone (38.1.2). Reducing the nitro groups in this compound with hydrogen using a palladium on carbon catalyst gives 3,4-diaminobenzophenone (38.1.3).

The second reagent, N-methoxycarbonyl-S-methylthiourea (38.1.4), is made by reacting methyl chloroformate with S-methylthiourea.

Metabolism

Primarily hepatic. Primary metabolite is 2-amino-5-benzoylbenzimidazole, but also metabolized to inactive hydroxy and hydroxyamino metabolites. All metabolites are devoid of anthelmintic activity.

References

[1]. seo bs, cho sy, kang sy, et al. anthelmintic efficacy of methyl-5-benzoylbenzimidazole-2-carbamate(mebendazole) against multiple helminthic infections. kisaengchunghak chapchi. 1977 jun;15(1):11-16.
[2]. morgan um, reynoldson ja, thompson rc. activities of several benzimidazoles and tubulin inhibitors against giardia spp. in vitro. antimicrob agents chemother. 1993 feb;37(2):328-31.
[3]. doudican n, rodriguez a, osman i, et al. mebendazole induces apoptosis via bcl-2 inactivation in chemoresistant melanoma cells. mol cancer res. 2008 aug;6(8):1308-15.
[4]. mukhopadhyay t, sasaki j, ramesh r, et al. mebendazole elicits a potent antitumor effect on human cancer cell lines both in vitro and in vivo. clin cancer res. 2002 sep;8(9):2963-9.
[5]. sasaki j, ramesh r, chada s, et al. the anthelmintic drug mebendazole induces mitotic arrest and apoptosis by depolymerizing tubulin in non-small cell lung cancer cells. mol cancer ther. 2002 nov;1(13):1201-9.
[6]. larsen ar, bai ry, chung jh, et al. repurposing the antihelmintic mebendazole as a hedgehog inhibitor. mol cancer ther. 2015 jan;14(1):3-13.
[7]. aleyasin h, karuppagounder ss, kumar a, et al. antihelminthic benzimidazoles are novel hif activators that prevent oxidative neuronal death via binding to tubulin. antioxid redox signal. 2015 jan 10;22(2):121-34.