Fungi
Also known as mycoses
Very large and diverse group of microorganisms
Of major two types: yeasts and molds.
Mycotic Infections:
Cutaneous
Subcutaneous
Superficial
Systemic:
Can be life-threatening
Usually occur in immunocompromised host
Targets for Antifungal agents
- Generally these targets should be different from mammalians.
- Both human and fungi are eukaryotic, so not much difference could be
found.
- The most important difference is the presence of cell wall for fungi that is
not found in humans.
Cholesterol Ergosterol
Polyene membrane disrupters
- Polyenes: macrocyclic lactones with distinct hydrophilic and lipophilic
regions.
- Produced from Streptomyces species
- Hydrophilic: alcohol, carboxylic acids, sugar.
- Lipophilic: contain a pharmacophore of 4-7 conjugated double bonds.
- The number of the double bonds correlate directly to activity and inversely
to toxicity.
2- Amphotericin B:
- Heptaene derivative with low enough toxicity for I.V use, but still toxic
drug used with caution.
Amphotericin nephrotoxicity
Ergosterol Biosynthesis inhibitors
A- Azoles:
- The largest group of antifungal agents.
- Some used topically and others used systemically.
- some are orally bioavailable with broad spectrum properties.
- SAR:
- 5-membered ring with 2-3 Ns.
- side chain attached to N.
- At least has one aromatic ring.
- Mechanism of action:
- Act by inhibiting ergosterol synthesis by inhibiting CYP450 14-
α-demethylase, where the basic nitrogen N3 of the drug bind to heme
iron of the enzyme blocking the active site.
R R CO2 R
Fe-Cyt P-450
CO2H
Lanosterol Carboxylate Ergosterol
N Fe-Cyt P-450 N
N N Fe-Cyt P-450
- This new sterol structure does not have the shape and physical
properties of the normal ones, leading to permeability changes.
1. Ketoconazole:
Ketoconazole Metabolism:
- Deacylation.
- Aromatic hydroxylation.
Hydroxylation
Binds heme active site
Deacylation
Ergosterol Biosynthesis inhibitors
2- Itraconazole:
- Triazole derivative.
- Oral bioavailability depend on food and stomach pH.
- highly interfere with liver enzymes (serious drug drug
interactions).
3- Fluconazole:
- Equal bioavailability, oral and I.V.
- Could cross BBB (Why?).
- Weak inhibitor to some liver enzymes.
Ergosterol Biosynthesis inhibitors
B- Allylamines:
- They have limited spectrum of activity which is only used for
dermatophytes.
Epoxidase
Steps
Steps
HO HO
Ergosterol Lanosterol
Ergosterol Biosynthesis inhibitors
-Terbinafine:
- Topical and Oral.
- Active against many dermatophytes.
- Highly lipophilic.
- Extensively metabolized.
Ergosterol Biosynthesis inhibitors
C- Morpholines:
- Amorolfine:
- The only drug of this class, used topically.
- Act on Δ14 reductase enzyme, and Δ8, Δ7 isomerase
enzymes.
- produce non-similar compounds with different physical
properties, leading to cell leakage.
Miscellaneous mechanism of actions
- Flucytosine:
- Powerful agent for systemic infections.
- Taken up by fungal cells and interferes with
DNA synthesis
- Prodrug to produce 5-flurouracil.
- Griseofulvin:
- Orally taken for superficial infections.