Structureactivity Relationships

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The basic structural requirement for members of the azole class is a weakly basic imidazole or 1,2,4-triazole ring (pKa of 6.5-6.8) bonded by a nitrogen-carbon linkage to the rest of the structure. At the molecular level, the amidine nitrogen atom (N-3 in the imidazoles, N-4 in the triazoles) is believed to bind to the heme iron of enzyme-bound cytochrome P450 to inhibit activation of molecular oxygen and prevent oxidation of steroidal substrates by the enzyme. The most potent antifungal azoles possess two or three aromatic rings, at least one of which is halogen substituted (e.g., 2,4-dichlorophenyl, 4-chlorophenyl, 2,4-difluorophenyl), and other nonpolar functional groups. Only 2, and/or 2,4 substitution yields effective azole compounds. The halogen atom that yields the most potent compounds is fluorine, although functional groups such as sulfonic acids have been shown to do the same. Substitution at other positions of the ring yields inactive compounds. Presumably, the large nonpolar portion of these molecules mimics the nonpolar steroidal part of the substrate for lanosterol 14a-demethylase, lanosterol, in shape and size.

The nonpolar functionality confers high lipophilicity to the antifungal azoles. The free bases are typically insoluble in water but are soluble in most organic solvents, such as ethanol. Fluconazole, which possesses two polar triazole moieties, is an exception, in that it is sufficiently water soluble to be injected intravenously as a solution of the free base.

PRODUCTS Clotrimazole

1-(o-Chloro-a,a-diphenylbenzyl)imidazole (Lotrimin, Gyne-Lotrimin, Mycelex) is a broad-spectrum antifungal drug that is used topically for the treatment of tinea infections and candidiasis. It occurs as a white crystalline solid that is sparingly soluble in water but soluble in alcohol and most organic solvents. It is a weak base that can be solubilized by dilute mineral acids.

Clotrimazole is available as a solution in polyethylene glycol 400, a lotion, and a cream in a concentration of 1%. These are all indicated for the treatment of tinea pedis, tinea cruris, tinea capitis, tinea versicolor, or cutaneous candidiasis. A 1% vaginal cream and tablets of 100 mg and 500 mg are available for vulvovaginal candidiasis. Clotrimazole is extremely stable, with a shelf life of more than 5 years.

Although clotrimazole is effective against various pathogenic yeasts and is reasonably well absorbed orally, it causes severe gastrointestinal disturbances. It is also extensively protein bound and, hence, is not considered optimally bioavailable. Clotrimazole is not considered suitable for the treatment of systemic infections.

Econazole Nitrate

1-[2-[(4-Chlorophenyl)methoxy]-2-(2,4-dichlorophenyl)-ethyl]-1H-imidazole (Spectazole) is a white crystalline nitric acid salt of econazole. It is only slightly soluble in water and most organic solvents.

Econazole is used as a 1% cream for the topical treatment of local tinea infections and cutaneous candidiasis.

Butoconazole Nitrate

1-[4-(4-Chlorophenyl)-2-[(2,6-dichlorophenyl)-thio]butyl]-1h-imidazole (Femstat) is an extremely broad-spectrum antifungal drug that is specifically effective against c. albicans. It is supplied as a vaginal cream containing 2% of the salt. It is intended for the treatment of vaginal candidiasis.

Sulconazole Nitrate

Sulconazole Nitrate

1-[2,4-Dichloro-j8-[p-chlorobenzyl)thio]phenethyl]imida-zole mononitrate (Exelderm) is the white crystalline nitric acid salt of sulconazole. It is sparingly soluble in water but soluble in ethanol. The salt is used in a solution and a cream in 1% concentration for the treatment of local tinea infections, such as jock itch, athlete's foot, and ringworm.

Oxiconazole Nitrate

(Z)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanone-0-[2,4-dichlorophenyl)methyl]oxime mononitrate (Oxistat) is a white crystalline nitric acid salt. It is used in cream and lotion dosage forms in 1% concentration for the treatment of tinea pedis, tinea corporis, and tinea capitis.

Tioconazole

1-[2-[(2-chloro-3-thienyl)methoxy]2-(2,4-dichlorophenyl)-ethyl]-1H-imidazole (Vagistat) is used for the treatment of vulvovaginal candidiasis. A vaginal ointment containing 6.5% of the free base is available. Tioconazole is more effective against Torulopsis glabrata than are other azoles.

Miconazole Nitrate

1-[2-(2,4-Dichlorophenyl)-2-[2,4-dichlorophenyl]-methoxy]ethyl]-1H-imidazole mononitrate (Monistat, Micatin) is a weak base with a pKa of 6.65. The nitric acid salt occurs as white crystals that are sparingly soluble in water and most organic solvents.

The free base is available in an injectable form, solubi-lized with polyethylene glycol and castor oil, and intended for the treatment of serious systemic fungal infections, such as candidiasis, coccidioidomycosis, cryptococcosis, petriel-lidiosis, and paracoccidioidomycosis. It may also be used for the treatment of chronic mucocutaneous candidiasis. Although serious toxic effects from the systemic administration of miconazole are comparatively rare, thrombophlebitis, pruritus, fever, and gastrointestinal upset are relatively common.

Miconazole nitrate is supplied in various dosage forms (cream, lotion, powder, and spray) for the treatment of tinea infections and cutaneous candidiasis. Vaginal creams and suppositories are also available for the treatment of vaginal candidiasis. A concentration of 2% of the salt is used in most topical preparations.

Ketoconazole

1-Acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2(1H-imidazole-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine (Nizoral) is a broad-spectrum imidazole antifungal agent that is administered orally for the treatment of systemic fungal infections. It is a weakly basic compound that occurs as a white crystalline solid that is very slightly soluble in water.

The oral bioavailability of ketoconazole depends on an acidic pH for dissolution and absorption. Antacids and drugs such as H2-histamine antagonists and anticholinergics that inhibit gastric secretion interfere with its oral absorption. Ketoconazole is extensively metabolized to inactive metabolites, and the primary route of excretion is enterohe-patic. It is estimated to be 95% to 99% bound to protein in the plasma.

Hepatotoxicity, primarily of the hepatocellular type, is the most serious adverse effect of ketoconazole. Ketoconazole is known to inhibit cholesterol biosynthesis,47 suggesting that lanosterol 14a-demethylase is inhibited in mammals as well as in fungi. High doses have also been reported to lower testosterone and corticosterone levels, reflecting the inhibition of cytochrome P450-requiring enzymes involved in human steroid hormone biosynthesis.48 Cytochrome P450 oxidases responsible for the metabolism of various drugs may also be inhibited by ketoconazole to cause enhanced effects. Thus, ketoconazole causes clinically significant increases in plasma concentrations of cy-closporine, phenytoin, and terfenadine. It may also enhance responses to sulfonylurea hypoglycemic and coumarin anticoagulant drugs.

Ketoconazole 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 14a-demethylase49 indicated that the 2S,4R isomer was 2.5 times more active than its 2R,4S enantiomer. The trans--isomers, 2S,4S and 2R,4R, are much less active.49

Ketoconazole is recommended for the treatment of the following systemic fungal infections: candidiasis (including oral thrush and the chronic mucocutaneous form), coccid-ioidomycosis, blastomycosis, histoplasmosis, chromomyco-sis, and paracoccidioidomycosis. It is also used orally to treat severe refractory cutaneous dermatophytic infections not responsive to topical therapy or oral griseofulvin. The antifungal actions of ketoconazole and the polyene antibiotic amphotericin B are reported to antagonize each other.

Ketoconazole is also used topically in a 2% concentration in a cream and in a shampoo for the management of cutaneous candidiasis and tinea infections.

Terconazole cis-1-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)-1,3-dioxolan-4-yl)methoxy]phenyl]-4-(1 methylethyl)piperazine (Terazol), or terconazole, is a tria-zole derivative that is used exclusively for the control of vulvovaginal moniliasis caused by C. albicans and other Candida species. It is available in creams containing 0.4% and 0.8% of the free base intended for 7-day and 3-day treatment periods, respectively. Suppositories containing 80 mg of the free base are also available.

Itraconazole

4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piper-azinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one (Sporanox) is a unique member of the azole class that contains two triazole moieties in its structure, a weakly basic 1,2,4-triazole and a nonbasic 1,2,4-triazol-3-one.

Itraconazole is an orally active, broad-spectrum antifun-gal agent that has become an important alternative to keto-conazole. An acidic environment is required for optimum solubilization and oral absorption of itraconazole. Drugs such as H2-histamine antagonists and antacids, which reduce stomach acidity, reduce its gastrointestinal absorption. Food greatly enhances the absorption of itraconazole, nearly doubling its oral bioavailability. The drug is avidly bound to plasma proteins (nearly 99% at clinically effective concentrations) and extensively metabolized in the liver. Only one of the numerous metabolites, namely 1-hydroxyi-traconazole, has significant antifungal activity. Virtually none of the unchanged drug is excreted in the urine. Thus, the dosage need not be adjusted in patients with renal impairment. The terminal elimination half-life of itraconazole ranges from 24 to 40 hours.

The primary indications for itraconazole are for the treatment of systemic fungal infections including blastomycosis, histoplasmosis (including patients infected with human immunodeficiency virus [HIV]), nonmeningeal coccidioidomycosis, paracoccidioidomycosis, and sporotrichosis. It may also be effective in the treatment of pergellosis, disseminated and deep organ candidiasis, coccidioidal meningitis, and cryptococcosis.

In general, itraconazole is more effective and better tolerated than is ketoconazole. Unlike ketoconazole, it is not hepatotoxic and does not cause adrenal or testicular suppression in recommended therapeutic doses.14 Nonetheless, itraconazole can inhibit cytochrome P450 oxidases involved in drug and xenobiotic metabolism and is known to increase plasma levels of the antihistaminic drugs terfenadine and astemizole.

Fluconazole a-(2,4-Difluorophenyl)-a-(1H-1,2,4-triazol-1-ylmethyl)-1H-1,2,4-triazole-1 -ethanol or 2,4-difluoro-a,a-bis(1H-1, 2,4-triazol-1-ylmethyl)benzyl alcohol (Diflucan) is a water-soluble bis-triazole with broad-spectrum antifungal properties that is suitable for both oral and intravenous administration as the free base. Intravenous solutions of fluconazole contain 2 mg of the free base in 1 mL of isotonic sodium chloride or 5% dextrose vehicle.

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