Antifungal Agents “Antifungal agents are the drugs used against fungal infection and can be either fungistatic or fungicidal.” By: Rutvij A. Pokale (3087)

Introduction  Fungi-eukaryotic-cell wall contains chitin and ergosterol.  Fungi-divided into 4 classes : 1. Yeast 2. Yeast-like Fungi 3. Dimorphic Fungi 4. Moulds  Fungal infections are termed as Mycoses.  Fungal infection - 2 groups 1. Superficial Mycoses. 2. Deep-seated Mycoses.

Fungal Diseases  Dermatophytes- cause infections of skin, hair and nails- obtain nutrients by attacking keratin. Dermatophytic infections- known as tinea caused by Trichophyton, Microsporum and Epidermophyton.  Yeast- Candida albicans- cause vaginal yeast infection and oral yeast infection which occur in mucosal tissue.

Fungal Diseases  Thermally Dimorphic Fungi (Endemic Mycoses)- saprophytes-cause blastomycosis, coccidiomycosis, histoplasmosis, etc. Disease is caused through inhalation of contaminated dust- cause lung infection, circulatory system transport organism to other tissues- result in systemic infection.  Moulds- Aspergillus species cause infection in persons with suppressed immunity-cause infection through inhalation of spores, wounds & burns.

Chemical Classification of Antifungal Agents I.Antibioitics: 1.Polyenes:- e.g.: Amphotericin B, Nystatin 2.Echinocandins:- e.g.: Caspofungin, Micafungin 3.Heterocyclic Benzofuran:- e.g.: Griseofulvin II.Antimetabolites:- e.g.: Flucytosine III.Azoles: 1.Imidazole: i.Topical:- e.g.: Clotrimazole, Econazole ii.Systemic:- e.g.: Ketoconazole 2.Triazoles:- e.g.: Fluconazole, Itraconazole IV.Allylamines:- e.g.: Terbinafine, Tolnaftate V.Topical Agents:- e.g.: Benzoic acid, Zinc propionate, Salicylic acid

Azoles  Largest class of antimycotics available.  Some are used topically to treat superficial dermatophytic and yeast infection, whereas others are administered orally to treat systemic infections.  Characteristic chemical feature- 5-membered aromatic ring with 2 N atoms (imidazole) or 3 N atoms (Triazole)  Azole ring is attached through N to a side chain containing at least 1 aromatic ring.

SAR of Azoles  Require- weakly basic imidazole ring bonded by N-C linkage.  N-3 in imidazole and N-4 in triazole bind heme iron of enzyme-bound CYP450- inhibit activation of molecular O 2 & prevent oxidation of steroidal substrates.  Most potent azole possess 2 or 3 Aromatic rings, at least one of which is halogen substituted (e.g.: 4-chlorophenyl; 2,4-dichlorophenyl; 2,4-difluorophenyl) and other non- polar functional groups.  2 &/or 2,4-substitutions yield effective azole compounds.  Fluorine and Sulphonic acids yield most potent compounds.  Substitution at other position- inactive compound.

MOA of Azoles  At high concentration- fungicidal, at low concentration- fungistatic.  Fungicidal effect- damage cell membrane, loss of essential components such as K + and amino acids.  Fungistatic effect- inhibition of membrane-bound enzymes.  Lanosterol-14α-demethylase(CYP450 class enzyme) - target for azoles.

Antifungal agents Inhibit sterol-14α-demethylaseImpair biosynthesis of ergosterolAccumulates 14α-methylsterolDisrupt close packaging of acyl chain of phospholipids Impair function of membrane-bound enzyme system and ETC and thus inhibits growth of fungi

1. Ketoconazole  1-Acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2(imidazole-1-ylmethyl)- 1,3-dioxolan-4-yl]methoxy]phenyl]piperazine.  Broad spectrum antifungal agent- administered orally-treat systemic fungal infection such as Candidiasis, Blastomycosis, etc.  Used orally to treat cutaneous dermatophytic infections, used topically in 2% concentration in creams  Adverse effect: Hepatotoxicity.

2. Clotrimazole  1-[(2-chlorophenyl)(diphenyl)methyl)]- 1H-imidazole.  Broad spectrum antifungal agent.  Available as a solution in PEG400, lotion and cream in concentration of 1%  Used topically to treat tinea infections and candidiasis.  Not suitable for treatment of systemic infection.

Synthesis of Clotrimazole 2-Chlorotoluene 2-chlorotriphenylmethyl chloride Clotrimazole

3. Fluconazole

 Water soluble  It experiences little or no hepatic metabolism and excreted unchanged in urine.  Uses:  To treat systemic fungal infection  To treat candidiasis  To control esophageal and oropharyngeal candidiasis  Agent of choice in treatment of Cryptococcal meningitis  Preferred therapy in Coccidioidal meningitis

4. Itraconazole  4-[4-[4-[4-[(2,4-Dichlorophenyl)-2-1H-1,2,4-triazol-1-ylmethyl]- 1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl-2,4- dihydro-2-(1-methylpropyl)-3H-1,2,4-triazo-3-one.  Unique member of azole- contains two triazole moieties- a weakly basic 1,2,4-triazole and non-basic 1,2,4-triazol-3-one.

 It’s an orally active broad spectrum antifungal agent, important alternative to ketoconazole.  Metabolized in liver and one of the metabolite, 1- hydroxyitraconazole, has significant antifungal activity.  Used in treatment of systemic fungal infections, Candidiasis, Cryptococcosis, etc.

Griseofulvin  7-chloro-2’,4,6-trimethoxy-6’-methyl spiro[1-benzofuran- 2(3H)-1’-cyclohex-[2]-ene]-3,4’-dione  It is an antifungal antibiotic, fungistatic agent.  It is benzofuran derivative, a spiro compound.  It is a mitotic spindle poison, arrests metaphase, rapid dissolution of mitotic spindle  Used in treatment of tinea and ringworm infections.

Tolnaftate  O-naphthalen-2-yl-N-methyl-N-(3- methylphenyl)carbamothioate.  It is an allyamine antimycotic.  Thioester of β-naphthol, act against dermatophytes.  Available in concentration of 1% in creams, gels, powders, etc. for treatment of ringworm, athlete’s foot, etc.  Act as inhibitor of squalene epoxidase in susceptible fungi, so it is classified with allylamine antimycotics.

Flucytosine  4-amino-5-fluoro-2(1H)- pyrimidin-2-one  It is a Nucleoside Antifungal agent.  Orally active antifungal agent, very narrow spectrum of activity.  Indicated in treatment of serious systemic infection caused by strains of Candida and Cryptococcus species.

MOA of Flucytosine