ANTIFUNGALS!
Brian Tenner
CHEM 5398
22 April 2010
OUTLINE
Early Beginnings – Difficulties Treating
 Common Fungal Infections
 Antifungal Drugs
 Newer Therapies
 Assigned Reading/References/Homework

COMMON ANCESTOR?!
“I AM... A MUSHROOM; ON WHOM THE DEW OF HEAVEN DROPS NOW AND THEN.”
-JOHN FORD
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About 1408 Million Years
Ago, fungi and animals
phyla split
We are more closely related
to fungi then plants!
This will prove difficult for
one to treat mycotic
infections due to the
similarities between the
eukaryotic fungus and the
eukaryotic host (us! )
COMMON FUNGAL INFECTIONS!

Tinea –
 Athlete’s
Foot
 Jock
Itch
 Ringworm
 Versicolor
Yeast Infection
 Infection of the Lungs

 Aspergillosis
ATHLETE'S FOOT (TINEA PEDIS)

Symptoms: scaling,
flaking, and itching of the
feet.
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Caused by: Microsporum
and Trichophyton
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Treated with: various
allylamines and azoles,
miconazole nitrate, and
tolnaftate
RINGWORM

Symptoms: Scaling of the
skin, characteristic
circular rash
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Caused by: Microsporum
and Trichophyton
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Treated with: Miconazole,
Clotrimazole,
Ketoconazole
TINEA VERSICOLOR ()

Symptoms: Blotches of
differing pigmentation
around upper trunk
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Caused by: Malassezia
globosa
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Treated with: Topical
selenium sulfide,
Clotrimazole, Ciclopirox
olamine
YEAST INFECTION (CANDIDIASIS)
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Symptoms: Localized
infection (Thrush),
inflammation,
discomfort
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Caused by: Yeast Fungi
from genus Candida
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Treated with: nystatin,
ketoconazole,
fluconazole
ASPERGILLOSIS
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Symptoms: Delirium,
failure of organs, death!
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Caused by: Inhalation
of fungal spores from
genus Aspergillus
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Treated with: nystatin,
ketoconazole,
fluconazole,
capsofungin
Many of the common fungal infections described
affect the general population. There is a vaster
majority of fungi that cause serious harm to
people that are immunocompromised!!
COMMON ANTIFUNGALS
Amphotericin B
 Fluconazole
 Capsofungin
 Terbinafine
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Keep in mind: We need to target differences between our cell and
the fungal cell. Antibiotics will not work because of both cells
are eukaryotic and the medication could kill off the good gut
flora that competes with the fungus for nutrients. Treatments
usually include many combinations of different antifungals.
AMPHOTERICIN B


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(FUNGIZONE)
Known as a polyene macrolide
 38 – Membered Ring
Isolated 1955, market 1958
Amphiphilic!
 Anyone want to guess the Mech Of Action?!?!
AMPHOTERICIN B

Mech of Action!
Associates with the membrane and
causes leakage of Na, K, and Ca
across membrane. But how does it
differentiate between fungal cells
and human cells??
AMPHOTERICIN B

Instead of cholesterol in the cell membrane, fungal
cells have ergosterol. The heptaene portion of the
ring interacts strongly with ergosterol instead of
cholesterol.
vs
Cholesterol
Ergosterol
FLUCONAZOLE

(DIFLUCAN)
Bistriazole
Azole => Conjugated five-membered ring with at least 1 N and other
non carbon atoms (could be N)
Belongs to a larger class of well known antifungals – imidazoles
(Clotrimazole, Miconazole)
Fluconazole is newer though!
Imidazoles synthesized to treat both superficial AND systematic infections.
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
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Fluconazole
Clotrimazole
Miconazole
FLUCONAZOLE
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Mech of Action:
Specifically inhibits the cytochrome P450 fungal enzyme C14(alpha) demethylase. This enzyme is require in the 20 step
pathway [thank goodness we didn’t have to memorize this]
from lanosterol (intermediate in cholesterol synthesis) to
ergosterol. Fluconazole binds to the Fe center of the enzyme
(one of the nitrogens coordinates to the Fe).
CASPOFUNGIN
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(CANCIDAS)
Semisynthetic cyclic lipid-bearing polypeptide
Belongs to class of antifungals: echinocandins –
derived from the cyclic polypeptide.
Large MW, low oral bioavailability =>
administered intravenously.
Market 2001
CASPOFUNGIN

Mech of Action:
Potent inhibitor of the fungal enzyme 1,3-(beta)-D glucan
synthase. This enzyme catalyzes glucan polymerization (glucan
is just a polymeric sugar molecule), which is essential in the
synthesis of a fungi’s cell wall. Human cells do not possess a
cell wall, so the drug is effective.
TERBINAFINE



(LAMISIL)
Belongs to class of antifungals – the allylamines.
Treats mainly superficial infections.
Discovered by accident in 1974 - antifungal potential related
directly to the tertiary allylamine and the 1-substituted
naphthalene ring. Eventually developed terbinafine.
Butenafine
(Lotrimin)
Terbinafine
TERBINAFINE
Terbinafine

Mech of Action: All allylamines work similarly. They inhibit
ergosterol synthesis by inhibiting squalene epoxidase (oh
snap!), the enzyme that catalyzes the epoxide formation
between the 2 and 3 carbon of squalene. From this 2,3oxidosqualene intermediate, we produce lanosterol and
eventually ergosterol. *****
REFERENCES
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Molecules and Medicine. EJ Corey. John Wiley and
Sons: 2007
Recent Advances in the Chemistry of Anti-Infective
Agents. Editors PH Bentley and R. Ponsford. Royal
Society of Chemistry: 1993.
http://www.doctorfungus.org. DoctorFungus
Corporation
http://faculty.swosu.edu/scott.long/phcl/antifung.htm
. Long, Scott, Southwestern Oklahoma State
University
ASSIGNED READING

Mathew, Bijoy P.; Nath, Mahendra. Recent
approaches to antifungal therapy for invasive
mycoses. ChemMedChem (2009), 4(3),
310-323.
HOMEWORK
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1) Why is it so difficult to treat fungal infections?
2) The target of which biomolecule’s synthesis is the subject of many antifungal
drugs?
3) What are the main families of antifungal agents? Name a member of each
family.
4)
What is the most commonly employed antifungal agent to treat invasive fungal
infections? Describe its mechanism of action. What is the major side effect of this
agent?
5) What enzyme is the biological target of the azole antifungal agents? What is
the most common mechanism of fungal resistance to these agents?
6) The echinocandin caspofungin was approved by the FDA in 2001 for salvage
therapy in cases of resistant invasive aspergillosis. What is the most likely target of
these drugs?
7) Another class of antifungal agents is the allylamines, including
terbinafine. Draw the structure of terbinafine and define the allylamine
moiety. What is the biological target of allylamines?