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Brian Tenner CHEM 5398 22 April 2010. AntiFungals !. Early Beginnings – Difficulties Treating Common Fungal Infections Antifungal Drugs Newer Therapies Assigned Reading/References/Homework. Outline.

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Brian Tenner

CHEM 5398

22 April 2010

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
Common ancestor?!“I am... a mushroom; On whom the dew of heaven drops now and then.”-John Ford
  • 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
Common Fungal Infections!
athlete s foot tinea pedis
Athlete's Foot (Tineapedis)
  • Symptoms: scaling, flaking, and itching of the feet.
  • Caused by: Microsporumand Trichophyton
  • Treated with: various allylamines and azoles, miconazole nitrate, and tolnaftate
  • Symptoms: Scaling of the skin, characteristic circular rash
  • Caused by: Microsporumand Trichophyton
  • Treated with: Miconazole, Clotrimazole, Ketoconazole
tinea versicolor
TineaVersicolor ()
  • Symptoms: Blotches of differing pigmentation around upper trunk
  • Caused by: Malasseziaglobosa
  • Treated with: Topical selenium sulfide, Clotrimazole, Ciclopiroxolamine
yeast infection candidiasis
Yeast Infection (Candidiasis)
  • Symptoms: Localized infection (Thrush), inflammation, discomfort
  • Caused by: Yeast Fungi from genus Candida
  • Treated with: nystatin, ketoconazole, fluconazole
  • Symptoms: Delirium, failure of organs, death!
  • Caused by: Inhalation of fungal spores from genus Aspergillus
  • 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

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.

Common AntiFungals
amphotericin b fungizone
Known as a polyene macrolide
    • 38 – Membered Ring
  • Isolated 1955, market 1958
  • Amphiphilic!
    • Anyone want to guess the Mech Of Action?!?!
Amphotericin B (Fungizone)
amphotericin b
Mech of Action! Amphotericin B

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 b1
Instead of cholesterol in the cell membrane, fungal cells have ergosterol. The heptaene portion of the ring interacts strongly with ergosterol instead of cholesterol.Amphotericin b




fluconazole diflucan
    • 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.




Mech of Action:

Specifically inhibits the cytochrome P450 fungal enzyme C-14(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 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

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)


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 2,3-oxidosqualene intermediate, we produce lanosterol and eventually ergosterol. ***** Terbinafine


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.
  • Corporation
  • 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. Assigned Reading
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 echinocandincaspofungin 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?