Azole antifungals

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Chapter: Medicinal Chemistry : Antifungal Agents

Azole antifungals : 1. Miconazole (Micatin, Monistat) and Econazole 2. Ketoconazole (Nizoral) and Terconazole 3. Clotrimazole (Clotrimin, Mycelex) 4. Fluconazole (Syscan, Zocon, Flucos) 5. Butoconazole 6. Bifonazole 7. Zinoconazole


Antifungal Agents - Synthesis and Drug Profile

Azole antifungals

Mode of action: Azole antifungals inhibit sterol 14-α-demethylase, a microsomal cytochrome P450-dependent enzyme system, and thus, impair the biosynthesis of ergosterol for the cytoplasmic membrane and lead to the accumulation of 14-α-methyl sterols. These methylsterols may disrupt the packing of aryl chains of phospholipids, the functioning of certain membrane bound enzyme systems, such as ATPase and enzymes of the electron transport system, and thus, inhibiting the growth of fungi.

 

1. Miconazole (Micatin, Monistat) and Econazole


Synthesis

Synthesis of Miconazole and Econazole


Properties and uses of Miconazole: Miconazole is a white or almost white powder, very slightly soluble in water, sparingly soluble in methanol, and slightly soluble in alcohol. It is used as an antifungal agent.

Assay: Dissolve the sample in anhydrous acetic acid, with slight heating, if necessary, and titrate with 0.1 M perchloric acid. Determine the end point potentiometrically.

Dose: It is to be applied in the vagina at bedtime for seven days, and 200 mg vaginal suppositories for three days therapy.

Dosage forms: Miconazole cream I.P., B.P., Miconazole pessaries I.P., Miconazole tablets I.P., Miconazole and Hydrocortisone cream B.P., Miconazole and Hydrocortisone acetate cream B.P., Miconazole and Hydrocortisone ointment B.P.

Properties and uses of Econazole: Econazole is white or almost white crystalline powder, very slightly soluble in water, soluble in methanol, sparingly soluble in methylene chloride, and slightly soluble in alcohol. It is used as antifungal agent.

Assay: Dissolve the sample in anhydrous acetic acid and titrate with 0.1 M perchloric acid. Determine the end point potentiometrically.

Dose: It is available as a water insoluble cream (1%) to be applied twice a day.

Dosage forms: Econazole cream B.P., Econazole pessaries B.P.

 

2. Ketoconazole (Nizoral) and Terconazole


Metabolism of Ketoconazole: It is extensively metabolized by deacetylase of the microsomal enzymes and all the metabolites are inactive.

Properties and uses of Ketoconazole: Ketoconazole is a white powder, practically insoluble in water, soluble in methylene chloride and in methanol, sparingly soluble in alcohol. It is a racemic compound, consisting of the cis-2S, 4R, and cis-2R, 4S isomers. An investigation of the relative potencies of the four possible diastereomers of ketoconazole against rat lanosterol 1,4α-demethylase indicated that the 2S, 4R isomer was 2.5 times more active than its 2R, 4S enantiomer and the trans isomers, 2S, 4S, and 2R, 4R are much less active. Ketoconazole is an imidazole antifungal agent, which is a highly lipophilic compound. This property leads to high concentrations of ketoconazole in fatty tissues and purulent exudates. Ketoconazole is active against Candida spp and Cryptococcus neoformans.

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

Dose: It is administered as 200 mg scored tablets and 2% topical cream.

Synthesis


Metabolism of Terconzole: It is metabolized by CYP3A4 on oral administration.

Properties and uses of Terconzole: Terconazole is a white powder, practically insoluble in water, soluble in methylene chloride and in acetone, sparingly soluble in alcohol. It is a triazole derivative that is used exclusively for the control of Vulvovaginal moniliasis caused by Candida albicans and other Candida spp.

Assay of Terconzole: Dissolve the sample in a mixture of anhydrous acetic acid and volumes of methyl ethyl ketone (1:7) and titrate with 0.1 M perchloric acid. Determine the end point potentiometrically at the second point of inflexion.

Dose: The administered dose is 80 gm vaginal suppository at bedtime for three days; and 0.4% as vaginal cream for seven days.

 

3. Clotrimazole (Clotrimin, Mycelex)


Synthesis


Properties and uses: Clotrimazole is a white or pale yellow crystalline powder, practically insoluble in water, soluble in alcohol and in methylene chloride. It is used as an antifungal agent.

Assay: Dissolve the sample in anhydrous acetic acid and titrate with 0.1 M perchloric acid using naphtholbenzein as indicator until the colour changes from brownish-yellow to green.

Dose: The administered dose is usually as 100 mg tablet per day at bedtime for seven days for vaginal infection.

Dosage forms: Clotrimazole cream I.P., B.P., Clotrimazole pessaries I.P., B.P.

 

4. Fluconazole (Syscan, Zocon, Flucos)


Synthesis


Properties and uses: Flucanazole is a white hygroscopic crystalline powder, slightly soluble in water, and soluble in methanol and in acetone. It is a widely used bis-triazole antifungal agent. It is generally considered to be a fungi-static agent, and it is principally active against Candida spp and Cryptococcus spp. Fluconazole has useful activity against Coccidioides immitis, and is often used to suppress the meningitis produced by the fungus.

Assay: Dissolve the sample in anhydrous acetic acid and titrate with 0.1 M perchloric acid. Determine the end point potentiometrically.

Dose: The administered dose for superficial mucosal candidiasis for adults is 50 mg daily, which is increased to 100 mg daily. Recommended treatment duration is 7–14 days; in the case of oropharyngeal candidiasis, 14 days for atrophic oral candidiasis associated with dentures, 14–30 days for other mucosal candidal infections, including oesophagitis. In the case of children, more than 4 weeks the loading dose is 6 mg/kg followed by 3 mg/kg daily.

The administered dose for dermatophytosis, pityriasis versicolor, and candida infections for adults is 50 mg daily for up to 6 weeks.

The administered dose for cryptococcal infections, including meningitis, systemic candidasis for adults, initially is 400 mg followed by 200–400 mg daily; the maximum dose is 800 mg daily in the case of severe infections. In the case of cryptococcal meningitis, usual treatment duration is at least 6–8 weeks and may also be given via IV infusion. For children more than 4 weeks the dose is 6–12 mg/kg daily; same doses may be given every 72 h in neonates up to 2 weeks and every 48 h in neonates 2–4weeks old; the maximum dose is 400 mg daily.

 

5. Butoconazole


Synthesis


 

6. Bifonazole


Synthesis


Properties and uses: Bifonazole is a white crystalline powder, practically insoluble in water, and sparingly soluble in anhydrous ethanol. It is used as an antifungal agent.

Assay: Dissolve the sample in anhydrous acetic acid and titrate with 0.1 M perchloric acid. Determine the end point potentiometrically.

 

7. Zinoconazole


Synthesis:



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