Anti-fungals Med Chem

Question 1

What drugs are in polyenes drug class?

Answer 1

Amphotericin B, Nystatin

Question 2

What drug is this structure?

Answer 2

Amphotericin B

Question 3

What is the MoA of amphotericin B?

Answer 3

1. Binds to ergosterol (predominant sterol in fungal cell membranes)
   - Causes opening of membrane, leading to intracellular cations and protein leakage, destabilizing cell
2. Also withdraws ergosterol from membrane, causing same destabilization

Question 4

What is the reason for amphotericin B’s specificity toward fungal cells?

Answer 4

Mammalian cells contain cholesterol, not ergosterol

Question 5

What are the toxicities of amphotericin B?

Answer 5

1. Infusion-related: fever, chills, muscle spasms, vomiting
2. Renal damage
   - Reversible: reduced renal perfusion
   - Irreversible: Renal tubular injury

Question 6

What drug is in the allylamines drug class?

Answer 6

Terbinafine

Question 7

What drug is this structure?

Answer 7

Terbinafine

Question 8

What is the MoA of terbinafine?

Answer 8

Inhibits squalene epoxidase enzyme in ergosterol synthesis

Question 9

Describe what the result of terbinafine inhibiting squalene epoxidase does.

Answer 9

• Stops synthesis of squalene to ergosterol
• Fungal cell death from squalene accumulation, not loss of ergosterol

Question 10

What is terbinafine’s basis for selective inhibition of fungi?

Answer 10

It is 2,500 fold more selective for fungal enzyme compared to mammalian enzyme

Question 11

What drugs are in the azoles drug class?

Answer 11

Fluconazole, ketoconazole, voriconazole, isavuconazole, itraconazole

Question 12

What is the key structural feature in the azoles?

Answer 12

5-membered aromatic ring

Question 13

What is the structure of fluconazole?

Answer 13

Question 14

What is the structure of ketoconazole?

Answer 14

Question 15

What is the structure of itraconazole?

Answer 15

Question 16

What is the structure of voriconazole?

Answer 16

Question 17

What is the structure of isavuconazole?

Answer 17

Question 18

Which enzyme does the azoles inhibit?

Answer 18

CYP450 14alpha-demethylase

Question 19

What is the MoA of the azoles?

Answer 19

• Inhibits the binding and activation of molecular oxygen by CYP450 -> inhibits the conversion of lanosterol to ergosterol
• This inhibition causes release of toxic sterols that damages fungal cell membrane

Question 20

What is the azoles’ basis of selectivity?

Answer 20

Humans use same enzyme to make cholesterol, but fungal enzymes more sensitive

Question 21

What is the interaction of azoles on CYP450?

Answer 21

Azoles are metabolized by and inhibit liver CYP450 enzymes

Question 22

What is the effect of azoles inhibition on liver CYP450 enzymes?

Answer 22

Concentrations of drugs metabolized by CYP enzymes can be increased

Question 23

What is the structure of oteseconazole?

Answer 23

Question 24

What is the MoA of oteseconazole?

Answer 24

Selective inhibition of fungal enzyme CYP51 (a 14alpha-demethylase)

Question 25

What drugs are in the echinocandins drug class?

Answer 25

Caspofungin, micafungin, anidulafungin, rezafungin

Question 26

What is the general structure of echinocandins?

Answer 26

Cyclic hexapeptides with long, modified FA side chains

Question 27

What are the structures of caspofungin, micafungin, and anidulafungin?

Answer 27

Question 28

What is the MoA of echinofungins?

Answer 28

- Inhibits synthesis of beta(1-3) glucan, a cell wall component and this will destabilize cell membrane - beta(1-3) glucan synthase is target enzyme

Question 29

What is the echinocandins' basis for selective inhibition for fungi?

Answer 29

Mammalian cells lack beta(1-3) glucan synthesis and the synthase enzyme

Question 30

What is the structure of rezafungin?

Answer 30

Question 31

What drug class is ibrexafungerp?

Answer 31

Small molecule inhibitor of glucan synthase enzyme in fungi

Question 32

What is the structure of ibrexafungerp?

Answer 32

Question 33

What is the MoA of ibrexafungerp?

Answer 33

Triterpenoid antifungal that inhibits glucan synthase, depleting 1,3-beta-D-glucan

Question 34

What is ibrexafungerp's basis for selective inhibition for fungi?

Answer 34

It targets enzyme that isn't present in mammalian cells

Question 35

What is the structure of flucytosine?

Answer 35

Question 36

What is the MoA of flucytosine?

Answer 36

- Inhibits thymidylate synthase - Interferes with protein synthesis

Question 37

What is flucytosine's basis for selective inhibition for fungi?

Answer 37

Mammalian cells are unable to convert flucytosine to active metabolite

Question 38

Explain the reaction that is catalyzed by thymidylate synthase.

Answer 38

Thymidylate synthase converts dUMP to dTMP, which is needed for DNA synthesis

Question 39

How does flucytosine inhibit the reaction catalyzed by thymidylate synthase?

Answer 39

- Phosphorylated to form 5-FdUMP, which mimics dUMP - 5-FdUMP is a substrate, competitive inhibitor, and suicide inhibitor of thymidylate synthase - Thymidylate synthase is trapped in inactive form and cannot react with dUMP - No dTMP can be produced, which inhibits DNA synthesis

Question 40

Why is flucytosine nearly always administered with amphotericin B?

Answer 40

Fungal resistance can develop if conc. is too low

Question 41

What drug class does tavaborole belong to?

Answer 41

Oxaborole antifungals

Question 42

What drug is this structure?

Answer 42

Tavaborole

Question 43

What is the MoA of tavaborole?

Answer 43

Inhibits leucyl transfer RNA synthetase (LeuRS) which inhibits protein synthesis

Question 44

What is essential for tavaborole's activity?

Answer 44

The boron