Antifungals Med Chem

What is the MOA of azoles?

- The basic N3 atom of the azole binds to the heme iron of the CYP450 in the position normally occupied by the substrate: prevents substrate oxidation. - All the azoles inhibit the reaction of the 14α-demethylase,CYP51 - All the azoles bind to CYP51 about 1000 times more tightly than lanosterol (substrate). - Inhibition of CYP51 results in accumulation in the fungal cell membrane of sterols still bearing a 14α-methyl group - These sterols do not have the exact shape and physical properties of ergosterol. - The inhibition of CYP51 results in permeability changes, leaky membranes, and malfunction of membrane-imbedded proteins - These effects are taken together lead to fungal cell death

What are the two effects of inhibiting squalene epoxidase?

1. A decrease in total sterol content of the fungal cell membrane 2. A buildup within the fungal cell of the hydrocarbon squalene, which is itself toxic when present in abnormally high amounts

What is the MOA of echinocandins?

1. Echinocandins interfere with cell wall biosynthesis through inhibition of the enzyme β-1,3-glucan synthase. 2 .β-1,3-Glucan is an important polymer component of many fungal cell walls, and reduction in the glucan content severely weakens the cell wall, leading to rupture of the fungal cell. 3. One component of β-1,3-glucan synthase (Fks1P) is the main target of echinocandins, but detailed mechanism is unknown.

What is the MOA of Flucytosine?

1. Flucytosine itself is not cytotoxic but, rather, is a prodrug that is taken up by fungi and metabolized to 5-fluorouracil by fungal cytosine deaminase. 2. 5-FU is converted to 5-fluorodeoxyuridine, which is a thymidylate synthase inhibitor that interferes with both protein and RNA biosynthesis. 3. Human cells do not contain cytosine deaminase.

Why are echinocandins are relatively nontoxic to mammals?

1. The most notable difference between fungal and mammalian cells is that fungi have a cell wall and mammals do not. 2. Drugs interfering with cell wall biosynthesis would be expected to be relatively nontoxic to mammals.

What is the main component of Fungal and mammalian cell membrane

1.Fungal cell membrane contains ergosterol, while cholesterol is present in mammalian cell membrane.

What are the two main structural features of azoles?

1.The characteristic chemical feature of azoles from which their name is derived is the presence of a five-membered aromatic ring containing either two or three nitrogen atoms. 2. Imidazole rings have two nitrogen and triazoles three. In both cases, the azole ring is attached through N1 to a side chain containing at least one aromatic ring.

What are the advantages of the new generation of polyene analogs?

Amphotericin B analogs bind ergosterol but not cholesterol: Low toxicity. Fungi don't develop resistance.

What is the new MOA of polyenes?

Amphotericin exists primarily in the form of large, extramembranous aggregates that kill yeast by extracting ergosterol from lipid bilayers

Echinocandin B is a fermentation product of ............................. It is a cyclic peptide with a long lipophilic side chain, also called .............................

Aspergillus nidulans lipopeptide

How does the target specificity of azoles work?

Azoles bind to fungal CYP51 more tightly than to human CYP51 The differences of binding affinities between human and fungal CYP51s are the biochemical basis of the target specificity of azoles

What is the MOA of polyenes?

Binds to ergosterol within the fungal cell membrane resulting in depolarization of the membrane and the formation of pores The pores permit leakage of intracellular contents.

What are the three echinocandin derivatives? Is it natural, semi-synthetic or synthetic product

Caspofungin, micafungin, and anidulafungin semisynthetic

Similarities and difference between fungi and mammalian cells

Fungi are eukaryotic organisms that contain a nucleus in their cells. Fungal cells also have cell wall and membrane Mammalian cells also contain a nucleus but have no cell wall

is Amphotericin B a natural or synthetic product?

Natural

What is Amphotericin B produced from?

Streptomyces nodosus

What is nystatin isolated from?

Streptomyces noursei

What is the basis of developing of new azoles?

The binding pocket

What determines the relative selectivity of azols?

The non-binding part of the azole antifungal forms bonding interactions with the apoprotein in a manner that determines the relative selectivity of the drug for the fungal demethylases from different species, and versus other CYP450

Squalene epoxidase in mammals can be over 1,000 times less sensitive to allylamines than fungal enzymes. True/ False

True

Polyenes exhibit ......................... dependent killing

concentration

Polyenes favor ..................... over............................ in the binding

ergosterol over cholesterol

Azole antifungal agent reaction and primary target

lanosterol -> ergosterol cytochrome P450 enzyme, 14α-demethylase, also known as CYP51

Allylamines are employed only in the treatment of fungal infections of the ..................... and .........................

skin and nails

Ergosterol and cholesterol are two ...................... with overall ........................................ Their side changes and 3-D structures are slightly different .........................and .................................. including its biosynthetic pathway can be targets of antifungal agents with ....................... to mammalian cells.

sterols, similar structures Cell wall and ergosterol, low toxicity

What are the three structural features of polyene?

•The polyenes are macrocyclic lactones with distinct hydrophilic and lipophilic regions. •The hydrophilic region contains several alcohols, a carboxylic acid, and usually, a sugar. •The lipophilic region contains, in part, a chromophore of four to seven conjugated double bonds.