Antifungal Drugs

Alexandria University Collage of pharmacy Pharmaceutical Chemistry dept.

Prepared by: Mohamed Saad Gad Mohamed Rabee

Supervised by: Dr. Soaad Hawash

:Fungi is • Eukaryotic – a true nucleus • Do not contain chlorophyll • Have cell walls • Produce filamentous structures • Produce spores • Contain ergosterol • The Term mycosis (plural: mycoses) refers to conditions in which fungi pass the resistance barriers of the human or animal body and establish infections.

Classification of antifungals Polyene anti fungals:A polyene is a circular molecule consisting of .a hydrophobic and hydrophilic region The polyene antimycotics bind with sterols in the fungal cell membrane, principally ergosterol. As a result, the cell's contents leak out (usually the hydrophilic contents) and the cell dies. Animal cells contain cholesterol instead of ergosterol and so they are much less susceptible. (Note: as polyene's hydrophobic chain is reduced, its sterol binding activity is increased. Therefore, increased reduction of the hydrophobic chain may result in it binding to

Classification of antifungals Examples: * Natamycin -- 33 Carbons, binds well to ergosterol * Rimocidin * Nystatin * Amphotericin B

Classification of antifungals Non polyenes antifungals Griseofulvin: The drug binds to tubulin, interfering with microtubule function, thus .inhibiting mitosis It binds to keratin in keratin precursor cells and makes them resistant to fungal infections. It is only when hair or skin is replaced by the keratin-griseofulvin complex that the drug reaches its site of action. Griseofulvin will then enter the dermatophyte through energy dependent transport processes and bind to fungal microtubules. This alters the processing for

Classification of antifungals Imidazole and triazole antifungals The imidazole and triazole antifungal drugs inhibit the enzyme cytochrome P450 14αdemethylase. This enzyme converts lanosterol to ergosterol, and is required in fungal cell membrane synthesis. These drugs also block steroid synthesis in .humans (Miconazole (Miconazole nitrate * Clotrimazole - marketed as Lotrimin * The triazoles are newer, and are less toxic and more effective Fluconazole * Itraconazole *

Classification of antifungals Allylamines Allylamines inhibit the enzyme squalene epoxidase, another enzyme required for :ergosterol synthesis "Terbinafine - marketed as "Lamisil* Amorolfine* Naftifine - marketed as "Naftin*

:Classification of antifungals

Echinocandins Echinocandins inhibit the synthesis of glucan in the cell wall, probably via the enzyme 1,3-β :glucan synthase Anidulafungin Caspofungin Micafungin

Polyene antifungal: Structure activity relationship (SAR): hydropho bic

hydrophil ic

Amphtericin B 

Nystatin 

:Polyene antifungal :(Structure activity relationship (SAR

The polyene antibiotic produced by actinomycetes contain a large lactone ring with 4 to 7 unsubstituted conjugated double bond . The conjugated system are usually in all-trans configuration so that the ring contains a planner lipophilic segment and a less rigid hydrophilic portion. With increase conjugation (double bond) the activity and toxicity will increase. The polyenes have polyhydroxyl groups.

:Polyene antifungal Structure activity relationship (SAR): •Amphotericin B have 7conjugated double bond while nystatin have 6 conjugated double bond so, amphotericin B more active and more toxic. •Most polyene antifungal drugs are macrocyclic lactones. •Ring sizes varying from 12 to 37 atoms in size .

Amphtericin B & Nystatin Mechanism of action (MOA):

Amphtericin B & Nystatin

Amphtericin B Some Trade Names: Fungilin® Fungizone® Amphotericine B® AmBisome® Fungisome® Amphocil® Amphotec®

Amphtericin B Uses and spectrum: Amphotericin B for injection (IV) administered primarily to patients with progressive, potentially lifethreatening fungal infections such as:  Aspergillosis  cryptococcosis (torulosis)  North American blastomycosis  systemic candidiasis  coccidioido-mycosis  histoplasmosis  zygomycosis including mucormycosis Its spectrum is the broadest of all antifungals.

 Griseofulvin Brand Names: Fulvicin P/G, Fulvicin U/F, Grifulvin V, GrisPEG, Grisactin 250, Grisactin 500, Grisactin Ultra Penicillium niciklium griseofulvum. Spectrum of activity and Resistance: 1) Effective against various species of Trichophyton, Microsporum, and Epidermophyton 2) Not effective against candida and bacteria

Structure Activity Relationship: • Four possible stereoisomers only (+)enantiomer is active • Cl replaced by F → same activity • Cl replaced by Br or H → ↓ activity • Placement of the halogen on C5 → ↓ activity • Replacement of CH3O on ring C with either propoxy or butoxy functions → ↑ activity

Griseofulvin Mechanism of action : Binds to keratin disrupts the cell's mitotic spindle structure cause defective DNA synthesis interferes with tubulin polymerization Resistance: is due to alteration of the drug's target site, by mutation of ribosome sequences.

Griseofulvin Uses: is effective against dermatophytes but yeast-like fugi are less susceptible. Tinea capitis (ringworm of the scalp) Tinea cruris (ringworm of the high) Tinea corporis (ringworm of the body( Tinea unguium (onychomycosis) Tinea barbae (barber's itch) Tinea : species of fungus that causes ringworm

 Butenafine hydrochloride Pharmacology Odorless white crystalline powder that , is freely soluble in methanol , ethanol and chloroform , and slightly soluble in .water

structure-activity relationships Efficacy may be related to an interaction with cell membrane phospholipids and permeabilization of the fungal cell wall. High lipophilicity could account for the long duration of action

Indications Butenafine is indicated for the topical • treatment of tinea (pityriasis) versicolor due to M. furfur, as well as athlete’s foot (Tinea pedis), ringworm (Tinea corporis) and jock itch (Tinea cruris) due to E. floccosum, T. mentagrophytes, T. rubrum, and T. .tonsurans

:Some Trade Names • Lotrimin ultra®

Anidulafungin • Anidulafungin is an anti-fungal drug manufactured by Pfizer.

• . It is a member of the class of

anti-fungal drugs known as the echinocandins.

mechanism of action Mechanism of action is by inhibition of (1→3)β-D-glucan synthase, which is (1→3) an important component of the fungal cell wall.

:Some Trade Names • Cancidas ®

Ciclopirox Ciclopirox olamine is a• synthetic antifungal agent for topical dermatologic treatment of superficial .mycoses

Mechanism of action It acts by inhibiting the membrane transfer system by interrupting the Na+ K+ ATPase.

:Some Trade Names • Penlac Nail Laquer®

Tolnaftate Tolnaftate is a synthetic

over-the-counter anti-fungal agent. It may come as a cream, powder, spray, or liquid aerosol, and is used to treat jock itch, athlete's foot and ringworm.

Mechanism of action o it is believed to inhibit the squalene epoxidase, an important enzyme in the biosynthetic pathway of ergosterol

:Some Trade Names • Ezon-T ® • Tineacure ®

Haloprogin Haloprogin is an antifungal drug

used to treat athlete's foot and other fungal infections. It is marketed in creams under the trade names Halotex, Mycanden, Mycilan, and Polik.

Action It was marketed over the counter primarily to treattinea infections of the skin. The mechanism of . action isunknown

Uses Is used to treat skin infections such as athlete's foot, jock itch, ringworm, and other fungal skin .(infections (candidiasis Haloprogin is an antifungal that works by preventing the growth .of fungus

Flucytosine • It is structurally related to the cytostatic fluorouracil and to floxuridine .

Mechanisms of action  The drug is intrafungally converted

into the cytostatic fluorouracil that undergoes further steps of activation and finally interacts as 5fluorouridinetriphosphate with RNA biosynthesis and disturbs the building of certain essential proteins.

Mechanisms of action  Is the conversion into 5-

flourodeoxyuridinemonophosph ate which inhibits fungal DNA synthesis.

resistance • Resistance is quite commonly

seen as well in treatment naive patients and under current treatment with flucytosine. • In different strains of Candida resistance has been noted to occur in 1 to 50% of all specimens obtained from patients.