Benzimidazoles: Mebendazole (Vermox), Flubendazole, Albendazole (Valbazen, Bentex, Zental), Thiabendazole (Mintezol) - 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.
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.
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.
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.
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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