Antifungal agents
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.
- Other targets are:
-
Inhibitors of DNA synthesis.
Disruption of mitotic spindle.
Interfere with metabolism.
- The most exploited difference is the nature of sterols:
- Important components of cell membrane for proper function of cell membrane
enzymes and ion transporter proteins.
Targets for Antifungal agents
- Mammalians contain cholesterol while fungi posses ergosterol.
- The difference is in the side chain of ergosterol which is more flat
compared to cholesterol;
- A difference that is responsible for providing selectivity for the majority of
antifungal agents.
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.
- Amphotericin is 10X more active which can be taken systemically.
- Mechanism of action: have affinity to ergosterols containing membranes,
then inserted in the cell membrane, disrupts its function, leak of cell
components.
Amphotericin
Polyene membrane disrupters
1- Nystatin:
- A tetraene agent that used topically.
- No oral absorption, so used orally for mouth and GIT infections.
2- Amphotericin B:
- Heptaene derivative with low enough toxicity for I.V use, but still toxic
drug used with caution.
- It does not cross BBB, so used intrathecally of brain fungal infections.
- The main side effect is nephrotoxicity, reduced by formulation change.
- Liposomal encapsulation was found to target infected tissues as the
capillary size at the infected areas is larger, so release the drug specifically
at that area.
Nystatin
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 14α-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
Carboxylate
Lanosterol
N
N
Fe-Cyt P-450
Ergosterol
N
N
Mechanism of action of Azoles
Fe-Cyt P- 450
Ergosterol Biosynthesis inhibitors
- Inhibition will lead to accumulation of sterols with extra methyl
group.
- This new sterol structure does not have the shape and physical
properties of the normal ones, leading to permeability changes.
- Selectivity to mammalian C450 compared to the fungal one is 1:1000,
and even, most of azoles considered mammalian C450 inhibitors which
lead to serious drug-drug interactions in some cases.
- Systemic azoles are : Ketoconazole, Itraconazole, Fluconazole and
voricanazole.
- Non-systemic azoles are : Clotrimazole, Oxiconazole and miconazole.
Ergosterol Biosynthesis inhibitors
1.
Ketoconazole:
- Imidazole derivative, that is
orally active for systemic infections.
- Depends mainly on low stomach pH for absorption.
- Inhibit C450 causing serious drug-drug interactions.
- All its metabolites are inactive and mainly used topically.
Ergosterol Biosynthesis inhibitors
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.
- Includes: Naftifine, Terbinafine, and Tolnaftate
- Mechanism of action: inhibit squalene epoxidase,
- leading to build up of squalene that it self is toxic
compound.
- and also lead to reduction of sterol levels in cell membrane,
leading to cell lysis.
- Mammalian squalene epoxidase is less sensitive to these drugs.
Squalene
Epoxidase
O
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.
- Not used topically.
- Bind to protein tubulin.
- Interfere with cell division.
O
O
NH2
F
N
O
N
H
Cytosine
Deaminase
HN
O
F
HN
F
N
H
5-Flurouracil
O
O P O
O
O
N
O
OH
5-Flurodeoxyuridine
monophosphate