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 Mycoses:
Mycoses are classified according to the
tissue levels initially colonized:
 Superficial mycoses - limited to the
outermost layers of the skin and hair.
 Cutaneous mycoses - extend deeper
into the epidermis, as well as invasive
hair and nail diseases. These diseases
are restricted to the keratinized layers of
the skin, hair, and nails. The organisms
that cause these diseases are called
dermatophytes.
Classification of Mycoses:
 Subcutaneous mycoses - involve the
dermis, subcutaneous tissues, muscle, and
fascia. These infections are chronic and can
be initiated by piercing trauma to the skin,
which allows the fungi to enter.
 Systemic mycoses due to primary
pathogens - originate primarily in the lungs
and may spread to many organ systems.
Classification of Mycoses:
 Systemic mycoses due to opportunistic
pathogens - infections of patients with immune
deficiencies who would otherwise not be
infected. Examples of immunocompromised
conditions include AIDS, alteration of normal
flora by antibiotics, immunosuppressive
therapy, and metastatic cancer. Examples of
opportunistic mycoses include Candidiasis,
Cryptococcosis and Aspergillosis.
Another example of a fungal infection is
Tinea versicolor: Tinea versicolor is a fungus
infection that commonly affects the skin of
young people
Treatment
Unlike bacteria, both fungi and humans are
eukaryotes. Thus fungal and human cells are
similar at the molecular level. This means it is
more difficult to find a target for an antifungal
drug to attack that does not also exist in the
infected organism.
Antifungal drugs are used to treat mycoses.
Depending on the nature of the infection, a
topical or systemic agent may be used.
Photochemotherapy or photopheresis is a
technique used at major medical centers for
the treatment of mycosis
Treatment
Photochemotherapy

Shown is close up of
surgeons' hands in an
operating room with a
"beam of light" traveling
along fiber optics for
photodynamic therapy
Treatment
photopheresis is a form of apheresis in which
blood is treated with photoactivable drugs
which are then activated with ultraviolet light.
Apheresis (Greek: "to take away") is a medical
technology in which the blood of a donor or
patient is passed through an apparatus that
separates out one particular constituent and
returns the remainder to the circulation.
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 cholesterol, making it toxic to animals.)
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 mitosis and also
underlying information for deposition of fungal cell
walls.
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
Trade names:
Fungilin®
Fungizone®
Abelcet®
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.
Amphtericin B
Side effects:
acute reaction:
 fever
 shaking chills
 hypotension
 anorexia
 nausea
 vomiting
 headache
 dyspnea
 tachypnea
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
Griseofulvin
Side effects:
Skin rashes
Dizziness
Fatigue
Headache
Vomiting
Swelling
Loss of taste sensation
Tingling in the hands or feet
Oral thrush (yeast infection of the mouth)