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Antifungal agents Fungi Also known as mycoses Very large and diverse group of microorganisms Of major two types: yeasts and molds. Mycotic Infections:

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Presentation on theme: "Antifungal agents Fungi Also known as mycoses Very large and diverse group of microorganisms Of major two types: yeasts and molds. Mycotic Infections:"— Presentation transcript:

1 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

2 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.

3 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. CholesterolErgosterol

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5 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.

6 Amphotericin

7 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.

8 Nystatin Amphotericin nephrotoxicity

9 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 CYP α-demethylase, where the basic nitrogen N3 of the drug bind to heme iron of the enzyme blocking the active site.

10 Mechanism of action of Azoles

11 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.

12 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.

13 Ergosterol Biosynthesis inhibitors Ketoconazole Metabolism: - Deacylation. - Aromatic hydroxylation. Hydroxylation Binds heme active site Deacylation

14 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.

15 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.

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17 Ergosterol Biosynthesis inhibitors -Terbinafine: - Topical and Oral. - Active against many dermatophytes. - Highly lipophilic. - Extensively metabolized.

18 Ergosterol Biosynthesis inhibitors C- Morpholines : - Amorolfine: - The only drug of this class, used topically. - Act on Δ 14 reductase enzyme, and Δ 8, Δ 7 isomerase enzymes. - produce non-similar compounds with different physical properties, leading to cell leakage.

19 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.

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