General Description
White to slightly yellow powder. Pleasant taste. Practically water insoluble.
Reactivity Profile
MEBENDAZOLE(31431-39-7) 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.
Air & Water Reactions
Insoluble in water.
Fire Hazard
Flash point data for this chemical are not available; however, MEBENDAZOLE is probably combustible.
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 (IC
50 = 0.19 μM for
Giardia in vitro).
1,2 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.
3,4,5 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.
6 Additionally, mebendazole has been shown to stabilize the transcriptional activator HIF-1α and its downstream targets, abrogating oxidative neuronal death in primary neurons.
7
Chemical Properties
White Amorphous Powder
Originator
Vermox,Ortho,US ,1975
Uses
Anthelmintic (Nematodes)
Uses
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.
Definition
ChEBI: A carbamate ester that is methyl 1H-benzimidazol-2-ylcarbamate substituted by a benzoyl group at position 5.
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
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
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
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.
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.
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.
Drug interactions
Potentially hazardous interactions with other drugs
Cimetidine: possibly inhibits metabolism of
mebendazole.
Antiepileptics: phenytoin, carbamazepine and
phenobarbital: lower mebendazole concentrations,
only relevant when being used in high doses for
echinococcosis.
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.
