Benzimidazole carbamates

Chemical Name (5-benzoyl-1 H-benzimidazol-2-yl)carbamic acid methyl ester Common Name Methyl-5-benzoyl-2-benzimidazole carbamate... 

Other chemicals evaluated but not yet adopted commercially include organophosphorus compounds, triphenyltin compounds, quaternary ammonium salts, imidazoles, benzimidazoles, carbamates and the precocene anti-juvenile hormones [517]. Although none of the above has found use as an insect-resist agent, several have been used as antimicrobial agents for textiles. 

Methylbenzimidazole, see 2-Nitroaniline Methyl 2-benzimidazole carbamate, see Benomvl Methyl benzoate, see Sulfometuron-methvl 4-Methyl-2//-l-benzopyran-2-one, see Naphthalene o-Methylbenzoquinone, see Aminocarb p-Methylbenzoquinone, see Toluene... 

Q90 Mebendazole is not suitable for v/omen knov/n to be pregnant. Mebendazole, v/hich is a benzimidazole carbamate derivative, has shov/n toxicity in rats. 

Mebendazole is a benzimidazole carbamate derivative that is used for the treatment of threadworm, roundworm, whipworm and hookworm infections. It is not recommended for women who are pregnant and in children under 2 years because the manufacturer reports that toxicity in animal studies has been reported. 

Mechanism of Action A benzimidazole carbamate anthelmintic that degrades parasite cytoplasmic microtubules, irreversibly blocks cholinesterase secretion, glucose uptake in helminth and larvae (depletes glycogen, decreases ATP production, depletes energy). Vermicidal. Therapeutic Effect Immobilizes and kills worms. Pharmacokinetics Poorly and variably absorbed from GI tract. Widely distributed, cyst fluid and including cerebrospinal fluid (CSF). Protein binding 70%. Extensively metabolized in liver. Primarily excreted in urine and bile. Not removed by hemodialysis. Half-life 8-12 hr. 

Albendazole (9.117), a benzimidazole carbamate, is a broad-spectrum oral antihelminthic used for cysticercosis, ascariasis, pinworm infestation, and hookworm infestation. It is thought to work by blocking microtubule synthesis in the nematode, subsequently impairing glucose uptake. 

Albendazole is a benzimidazole carbamate. After oral administration, it is erratically absorbed (increased with a fatty meal) and then rapidly undergoes first-pass metabolism in the liver to the active metabolite albendazole sulfoxide. It reaches variable maximum plasma concentrations about 3 hours after a 400-mg oral dose, and its plasma half-life is 8-12 hours. The sulfoxide is mostly protein-bound, distributes well to tissues, and enters bile, cerebrospinal fluid, and hydatid cysts. Albendazole metabolites are excreted in the urine. 

The benzimidazole group of anthelminthics is derived from the simple benzimidazole nucleus and includes the thiabendazole analogues and the benzimidazole carbamates. Substitution of side chains and radicals on the benzimidazole nucleus gives rise to the individual members of this group (Fig. 4.1). 

A number of benzimidazoles exist as prodrugs their anthelminthic activity is due to the fact that they are metabolized in the animal body to the biologically active benzimidazole carbamate nucleus. Due to their relatively slower excretion rates, the newer insoluble benzimidazoles have fairly long withdrawal periods for edible tissues and milk in contrast to the less effective and more rapidly excreted thiabendazole analogues. Strict compliance with withdrawal periods is always necessary because of the potentially toxic and teratogenic effects of some of the benzimidazoles and their metabolites. 

Since all members of the benzimidazole anthelminthics except thiabendazole contain a benzimidazole carbamate moiety, attempts have been made to produce antibodies recognizing this structure (19). Most successful was an approach in which a carboxylated analogue of albendazole was used as hapten and coupling to the carrier protein was performed using (V-hydroxysuccinimide and morpholi-noethyl isocyanide in the presence of dimethylamino pyridine. 

Several related analogues of the benzimidazoles are also anthelmintics including the imidazopyridine (5), tioxidazole (6), and the prodrugs, thiophanate (7) and febantel (8). However, although the benzimidazoles and related anthelmintics have proved a rich source of drugs, there is now evidence of widespread resistance to them, particularly in sheep parasites. Moreover, some benzimidazole carbamates are suspect in respect of teratogenicity and mutagenicity. 

In 1966 the second modern broad spectrum anthelmintic, tetramisole (9), was introduced by Jannsen. The discovery of this drug followed the observation that the thiazothienol (10) was metabolized to an active compound in chickens. This was shown to be the thiazothielite (11) which led ultimately to the discovery of tetramisole (9). Later investigations showed that most of the activity of tetramisole (9) was due to the L-isomer, levamisole, which was more potent and less toxic than the D-isomer. Since their introduction, tetramisole (9) and levamisole have probably become the most widely used anthelmintics against a broad range of nematodes in pigs, sheep and poultry. Furthermore, unlike most benzimidazole carbamates, which are rather insoluble and must be given as an oral drench, levamisole may be given by the more convenient injectable route at a dose of 7.5 mg kg-1. 

Carbamates are substituted esters of carbamic acid (NH2COOH) with aliphatic or aromatic substituents on the oxygen and nitrogen atoms. Carbamate insecticides have an aryl or oxime N-methylcarbamate structure, and their mode of action is based on the inhibition of the enzyme acethylcholine esterase (1). However, this inhibition is reversible, and recovery from sublethal doses occurs rapidly. Some carbamate fungicides have a dithio, bisdithio, or benzimidazole carbamate basic structure, and dithiocarbamate fungicides inhibit the enzyme aldehyde deshydro-genase (2). The herbicides have an /V-alkylthiocarbamate or A-phenylcarbamate structure and interfere with photosynthetic activity or affect meristematic activity or lipid metabolism (3). Representative structures of carbamate pesticides are shown in Fig. 1. 

Benzimidazole carbamates are usually analyzed by HPLC. Different stationary phases have been assayed, and alkyl-bonded-silica-based phases have generally been considered the most useful separation mode, although polymer-based columns performed better in separating benzimidazole fungicides (20). Buffered water and methanol (124,20) or acetonitrile (125) have been used as mobile phases. 

Benzimidazole carbamates have generally been determined by HPLC (20,124-126), although other methods have been reported based on enzyme immunoassay (147) or in gas chromatography (124). The commercial availability of high-performance thin-layer chromatography (HPTLC) plates with layers of very different polarities has improved the sensitivity, selectivity, and analytical precision of TLC, which has led to a reconsideration of the use of this technique for qualitative and quantitative analysis (54). 

T Gomyo, M Ozawa, S Kobayashi. Analytical method for determining the total content of methyl benzimidazole carbamate fungicides in water by column switching liquid chromatography mass spectrometry. Anal Sci 8 687-690, 1992. 

Vanden Bossche and de Nollin and others [12-14] have shown that benzimidazole carbamates, such as mebendazole, inhibit glucose uptake by helminths in vivo and in vitro-, this enhances endogenous glycogen utilization and is accompanied by reduction in glycogenesis. 

In 1971, the first benzimidazole derivative (1, HOE 33258) was reported to be an active microfilaricidal agent in L. carinii and D. immitis models [30]. After this report, very little effort was dedicated to this important problem for a decade. Recently, however, there has been renewed interest and activity which has shown some benzimidazole carbamates such as mebendazole (2), fluben-dazole (3), albendazole (4) and oxibendazole (5) to have significant macrofilari-... 

Table 4.1. ANTIFILARIAL ACTIVITY OF MEBENDAZOLE, FLUBENDAZOLE AND NEW CLASS OF BENZIMIDAZOLE CARBAMATES...

In general, benzimidazole-2-methyl carbamate derivatives (28) can be synthesized by the reaction of an appropriate diamine (26) with 1,3-dicarbo-methoxy-5-methylisothiourea (27) [43], This is the most general and economic synthesis for benzimidazole carbamates. However, the same reaction was less than satisfactory when the aza analogues of o-phenylenediamines (29) were used. In order to synthesize the aza analogues of mebendazole (2) or flubendazole (3), the reactions of methoxycarbonyl isothiocyanate (30) with a wide variety of diamines such as 3,4-diaminopyridines, 4,5-diaminopyrimi-dines, o-phenylenediamines have been investigated in the presence of dicyclo-hexylcarbodiimide [44, 45] and were found to be quite successful in the synthesis of carbamates (31). 

Common Name Methyl-5-benzoyl-2-benzimidazole carbamate Structural Formula ... 

A.M. Cummings, M.T. Ebron McCoy, J.M. Rogers, B.D. Barbee, and S.T. Harris, Developmental effects of methyl benzimidazole carbamate following exposure during early pregnancy. Fundam. Appl. Toxicol. 18 288, 1992. 

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