This document discusses various classes of antifungal agents including azoles. It describes the mechanism of action of azoles, which inhibit ergosterol biosynthesis by targeting cytochrome P450 14α-demethylase. Several individual azoles are mentioned such as clotrimazole, econazole, butoconazole, oxiconazole, tioconazole, miconazole, ketoconazole, terconazole, itraconazole and fluconazole. Their structures, uses in treating fungal infections and side effects are summarized.

1. Prof. K. SURESH KUMARProf. K. SURESH KUMAR
ANTIFUNGAL AGENTSANTIFUNGAL AGENTS
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KMCH COLLEGE OF PHARMACY
COIMBATORE
KMCH COLLEGE OF PHARMACY
COIMBATORE

2. ERGOSTEROL BIOSYNTHESISERGOSTEROL BIOSYNTHESIS

3. I Topical agent For
Dermatophytes
Fatty acids
Propionic acid
Zinc Propionate
Sodium Caprylate
Zinc Caprylate Undecylenic acid
Triacetin (glyceryl tri acetate)
Acids
Salicylic acis,
Benzoic acid
Phenols
Clioquinol
Haloprogin
Ciclopirox
II Nuclotides Flucytosine
III Antifungal Antibiotics
a) Polyenes Amphotericin -B
Nystatin
Natamycin
b) Benzofuron Griseofulvin
IV Allylamines Naftifine
Terbinafine
Tolnaftate
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4. V Azoles
a) Imidazoles
b) Triazoles
Clotrimazole
Econazole
Butoconazole
Sulconazole
Oxiconazole
Tioconazole
Miconazole
Ketoconazole
Terconazole
Itraconazole
Fluconazole
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5. AZOLES MECHANISM
 Cytochrome P450 14α Demethylase is the likely target for azoles.
CYP450 Possess a heme moiety, the basic electron pairs of the azole rings can occupy a
Binding site on p450.
There is no availability of 14α Demethylase to remove 14 α CH3 group from lanosterol
In ergosterol biosynthesis.
Results fungal cell membrane sterol still bearing 14 α CH3 group . It do not have an exact
Shape and Physical properties of the normal membrane ergosterol.
Results in permeability changes, leaky membrane & malfunction of memb-imbeded
Protein, leads to cell death.
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CLOTRIMAZOLE
ECONAZOLE
Broad Spectrum topical antifungal agent.
Tinea capitis, tinea pedis, tinea cruris
Tinea & candidias infections
1(O-chloro α, α diphenyl benzyl ) Imidazole
1[2 ( 4-chloro phenyl) methoxy] 2-(2,4 dichlorophenyl)
Ethyl] imidazole.
1% for local tinea infections cutaneous candidiasis

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BUTOCONAZOLE
..
1
2
3
4
OXICONAZOLE
1-4(4-chlorophenyl)-2-[2,6 dichlorophenyl] thio] butyl 1-H imidazole
Effective against C.albicans. It is intended for the treatment of
Vaginal candidiasis.
Used for tenia pedis, tinea corporis& tineacapitis

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TIOCONAZOLE
1-[2-chloro-3-thienyl) methoxy] 2(2,4 dichlorophenyl) ethyl] 1-H imidazole
Used for the treatment of vulvovaginal candidiosis
It is more effective against Torulopsis glabrata

9. MICONAZOLE
1-[2-(2,4 dichloro phenyl) 2-[2,4-dichloro phenyl] methoxy] ethyl] 1-H imidazole
It Is a Systemic Antifungal agents
It may be used for the treatment of serious systemic infections such as
 Cryptococciosis
 Candidiasis
 Coccidioid mycosis & ParaCoccidiosis
It may be used in chronic mucocutaneous Candidiasis
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10. SYNTHESIS
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11. KETOCONAZOLE
1-Acetyl-4[ [ 2-(2,4 dichlorophenyl) 2,1H imidazol-1yl) methyl)
1,3 dioxolan-4yl] methoxy phenyl piperazine.

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SYNTHESIS

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It inhibits lanosterol 14α Demethylase in mammals as well as fungi
It also inhibits CYP450 oxidase ( responsible for metabolism
of various drugs.
eg- Phenytoin, Cycloserine, Sulfonyl ureas & Coumarin
It is a racemic mixture cis2S,4R & cis 2R 4S isomer.
cis2S,4R is a potent isomer.
Ketoconazole and amphotericin-B are reported to antagonized each other.
USES:
Used in Systemic fungal infections such as
Candidiasis, Coccidiomycosis, Para occidiomycosis, Blastoplasmosis, Histoplasmosis,
Chromomycosis.

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TRIAZOLES
TERCONAZOLE
:
Cis-1-[4-[ [2-(2, 4 dichlorophenyl)-2-(1,2,4 triazolo-1yl methyl)
-1,3-dioxolan-4yl) methoxy] phenyl]-4(methylethyl)piperazine
Exclusively used for vulvovaginal moniliasis caused by Candida albicans

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ITRACONAZOLE
 It contains two triazoles.
 Weakly basic 1,2,4 triazole
 Non basic 1,2,4 triazole 3-one
 Acidic environment is required for oral absorption. H2 –Histamine antagonist & antacids
greatly decrease stomach acidity and reduce its absorption.
 Food greatly enhance its absorption.
 1-hydroxy itraconazole is a significant antifungal activity.

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USES:
It is more effective and better tolerated than Ketaconazole. Used for the treatment of
systemic fungal infections including
 Blastomycosis
 Histoplasmosis
 Coccidioidomycosis
 Para coccidioidomycosis
 Deep organ Candidiasis
 Meningitis
 Cryptococcosis.
USES:
It is more effective and better tolerated than Ketaconazole. Used for the treatment of
systemic fungal infections including
 Blastomycosis
 Histoplasmosis
 Coccidioidomycosis
 Para coccidioidomycosis
 Deep organ Candidiasis
 Meningitis
 Cryptococcosis.

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FLUCONAZOLE
α [ 2,4 difluoro phenyl] α [ 1H-1,2,4 triazol-1yl] 1H 1,2,4 triazole -1-ethanol
It is a bis triazole water soluble broad spectrum antifungal agents, suited for
both oral & IV adminstrations as free base.
 It penetrates to all body cavities including CSF.
 It is recommended for the treatment & prophylaxis of deep organ candidiasis.
 It also used to control esophageal candidiasis
 It is drug of choice for the treatment of Cryptococcal meningitis & prophylaxis
against Cryptococcosis in AIDS patient.

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