Alexandria University

Collage of pharmacy
Pharmaceutical Chemistry dept.

Supervised by:

Dr. Soad 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 14α-
demethylase. 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 life-
threatening 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, Gris-
PEG, 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
(1→3) synthase, which is
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 5-
fluorouridinetriphosphate 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.
Old antifungal agents