Benzimidazoles

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Chapter: Medicinal Chemistry : Anthelmintics

Benzimidazoles: Mebendazole (Vermox), Flubendazole, Albendazole (Valbazen, Bentex, Zental), Thiabendazole (Mintezol) - Synthesis and Drug Profile


Anthelmintics - Synthesis and Drug Profile

Benzimidazoles

Mode of action: These drugs act by blocking the glucose transportation in the parasites and lead to the depletion of glycogen storage of the intracellular microtubules in the cells of the worms, thereby arresting the nematodes and cell division in the metaphase. The major site of action is microtubular protein β tubilin of the parasite. These drugs are bound with β tubilin and inhibit the polymerization.

Metabolism: The parent compound is rapidly and almost completely metabolized by oxidative and hydrolytic processes.. The phase I oxidative reaction is commonly carried out by the cytochrome P450 catalyzed reaction, which may be followed by phase II conjugation.


 

Mebendazole (Vermox)


Synthesis

Step I. Synthesis of an intermediate-S-methyl thiourea arboxylate


Step II. Synthesis of Mebendazole


Metabolism: Mebendazole is metabolized by the reduction of the 5-carbonyl group to a secondary alcohol, which greatly increases the water solubility of this compound and thereby potentiates the excretion through urine. Secondary alcohol and amine are readily conjugated.


Properties and uses: Mebendazole is a white powder, practically insoluble in water, in alcohol, and in methylene chloride. It is used as an anthelmintic agent.

Assay: Dissolve the sample in anhydrous formic acid, add the mixture of anhydrous acetic acid and methyl ethyl ketone (1:7), and titrate against 0.1 M perchloric acid. Determine the end-point potentiometrically.

Dose: The administered oral dose is 100 mg tablets chewed daily.

 

Flubendazole


Synthesis


Properties and uses: Flubendazole is a white powder, practically insoluble in water, in alcohol, and in methylene chloride. It is used as an anthelmintic agent.

Assay: Dissolve the sample in anhydrous formic acid, add the mixture of anhydrous acetic acid and methyl ethyl ketone (1:7), and titrate against 0.1 M perchloric acid. Determine the end point potentiometrically.

 

Albendazole (Valbazen, Bentex, Zental)


Synthesis


Properties and uses: Albendazole is a white or faintly yellowish powder, practically insoluble in water and alcohol, soluble in anhydrous formic acid, very slightly soluble in methylene chloride. It is used as an anthelmintic agent.

Assay: Dissolve the sample in anhydrous formic acid, add anhydrous acetic acid, and titrate against 0.1 M perchloric acid. Determine the end point potentiometrically.

Dose: The dose for controlling cysticercus cellulose is 5 mg/kg thrice daily for 30 days.

 

Thiabendazole (Mintezol)


Metabolism: Thiabendazole is metabolized through aromatic hydroxylation at the fifth position catalyzed by CYP1A2. The resulting phenol is conjugated to 5-hydroxythiabendazole glucuronide.


Synthesis

Route I. From: o-Nitro aniline (or) 2-Nitrobenzenamine


Route II. From: Thiazolo nitrile


Properties and uses: It is a white, odourless, and tasteless powder, insoluble in water, slightly soluble in acetone, chloroform, or ether. It is used as a anthelminthic.

Dose: The dose orally is 25 mg/kg twice daily to a maximum of 3 g after meals. The dose for chewable tablets is 500 mg and oral suspension is 500 mg/5ml.

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