Med Chem

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1. Lanosterol
2. P-450
3. 14alpha-demethylase (Azole’s work on this)
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Cholesterol and Ergosterol. Notice the differences in structure and numbering system
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1. Squalene
2. Squalene Epoxidase (Allyl amines block this enzyme I.e. Terbinafine)
3. Squalene Epoxide
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Allyl Amine
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Terbinafine
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Naftifine
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Butenafine
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Tolnaftate
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Azole
N-1: Binds to appoprotein of 14alpha-demethylase
N-3: Bind to the ferric atom on heme group of the enzyme and prevents the introduction of the oxygen atom onto the sterol

binding of N1 will increase the binding affinity
binding N3 is important to inhibit the enzyme.

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Ketoconazole
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Clotrimazole
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Fluconazole

Enhanced activity due to Fluorines, higher plasma concentration and longer half-life

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1. Allyl Amine
2. Azole
3. Morpholine
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Nystatin

6 Chiral centers
OH’s make it hydrophillic
Long Carbon chain makes it lipophillic

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Echinocandin (Caspofungin, Anidulafungin, Micafungin) – group of cyclic peptides w/ long lipophilic side chain.
MOA = inhibits beta 1, 3 D – glucan synthase. decreases amt of beta 1,3 D glucan so it weakens the cell wall and leads to rupture of the fungal cell.
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Griseofulvin (may not need to know the structure but kow the MOA)

MOA = it binds to fungal RNA and inhibits cell wall biosynthesis. causes malformation of spindle microtubules important for proper mitosis. it protects keratin cells from spread of infection by blocking fungus from nutrients.

Methoxy on Far right ring provides lipophilicity. Butoxy or Propoxy improves activity but anything longer than that diminishes activity

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5-Fluorocytosine
Pro-drug

Well-absorbed and penetrates CSF (So do fluconazole)

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1. Flucytosine
2. Fungal cytosine deaminase – Converts it into 5-FU
3. Phosphorylation
4. 5-Fluorodeoxyuridine (5-FdUMP)

5-FdUMP then inhibits THYMIDYLATE SYNTHASE that will suppress RNA + Protein syntehesis.
5 FU may also be incorporated into RNA and result in inhibition of protein synthesis.
used in combo with AmB –> synergistic

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the only example of a morpholine

MOA = inhibits delta14 reductase and delta8,7 isomerase resulting in altered membranes as other ergosterol biosynthesis inhibitor antifungals.

its used in agriculture to treat plant disease.

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major = oxidation by CYP3A4
deacetylase causes hydrolysis of the N-acetyl group
x

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