MedChem of Antifungal drugs

Question 1

Antifungal drugs

• azoles prevent the conversion of lanosterol to ___
• terbinafine prevents the conversion of ___ to lanosterol
• flucytosine prevents the formation of ___ which form NA
• griseofulvin disrupts ___

Answer 1

• Ergosterol
• Squalene
• Purines
• microtubules

Question 2

Antifungal drugs: polyenes

Amphotericin B

MOA: Amphotericin B binds to ___ - predominant sterol in fungal cell membranes

Main features
- Natural product - produced by Streptomyces nodus
- ___ - has both acidic and basic groups
- Contains a ___ polyene region (bottom) and a ___ polyalcohol region (top) - amphiphilic
- ___ ring
- Fungi __

Answer 2

• ergosterol
• Amphoteric
• lipophilic, hydrophilic
• macrolide
• fungicidal

Question 3

Amphotericin B: Pharmacokinetics

Broad Spectrum - Drug of choice for life-threatening fungal infections

Poorly absorbed from GI tract
- fine for GI infections but needs to be ___ for systemic infection

Cerebrospinal levels 2-3% of blood levels ( ___ therapy needed for fungal meningitis)

Answer 3

• IV
• intrathecal

Question 4

Amphotericin B: Adverse effects

Toxicity is low enough to allow use, but still very toxic

Infusion-related
- Fever, chills, muscle spasms, vomiting, headache and hypotension
- Can be ameliorated by ___ rate of infusion
- Premedication with ___ and/or ___

___ damage
- Occurs in nearly all patients
- Reversible component - reduced renal ___
- Irreversible component - renal tubular injury
- Usually occurs after prolonged (>4 g) administration

___ abnormalities occasionally observed

Answer 4

• decreasing
• diphenhydramine, acetaminophen
• renal, perfusion
• liver

Question 5

Therapeutic applications

Systemic: ___
Superficial: ___

Answer 5

• Amphotericin B
• Nystatin

Question 6

Lipid Formulations of Amphotericin

• Lipid formulations reduce ___
• Lipids have intermediate affinity for amphotericin - higher than ___ , but lower than ___

Ambisome also reduces ___ toxicity
- Only AmBisome uses true ___

ABCD has less nephrotoxicity but potentially more ___

Answer 6

• nephrotoxicity
• cholesterol, ergosterol
• infusion, liposomes
• fever

Question 7

Ergosterol synthesis pathway

___ → squalene epoxide → ___ → ___

Answer 7

• squalene, lanosterol
• lanosterol, ergosterol

Question 7

Antifungal drugs: Allylamines

Terbinafine
- MOA: disrupts ergosterol synthesis by inhibiting ___ ___

Answer 7

• squalene epoxidase

Question 8

Antifungal drugs: Terbinafine

Fungicidal - death results from accumulation of ___ , not loss of ergosterol

• 2,500-fold selectivity for fungal enzyme compared to mammalian enzyme
• Mainly effective against dermatophytes, especially onychomycoses (more effective, less toxic, & requires shorter treatment than griseofulvin)
• Available for oral and topical administration
• ringworm, pityriasis versicolor, and fungal nail infections
• ___ (and several other brand names)

Answer 8

• squalene
• Lamisil

Question 9

Antifungal drugs: Terbinafine

• ___ (Lotrimin) and ___ (Lotrimin Ultra) are chemically similar to terbinafine & have same mechanism
• ___ (Tinactin; a thiocarbamate) has a different structure than terbinafine, but also inhibits squalene epoxidase
• Only available in topical preparations

Answer 9

• Naftifine, butenafine
• Tolnaftate

Question 10

Antifungal drugs: Azoles

MOA: Inhibition of ___ , one of 3 enzymes reponsible for converting lanosterol into ___
- Azoles inhibit the binding and activation of molecular ___ by cytochrome P450
- Largest class of antimycotics: >20 drugs
- Key feature: 5-membered aromatic ring
- Fungi ___

Answer 10

• 14 a-demethylase, ergosterol
• oxygen
• Fungistatic

Question 11

Azole MOA depicted - Accumulation of toxic sterols incell membrane

Answer 11

inhibits 14-alpha-demethylase

Question 12

Azoles

T or F: Humans use same 14-alpha-demethylase enzyme to make cholesterol
for our cell membranes

Answer 12

TRUE
- fungal enzyme is more sensitive to azoles tho
- However, azoles inhibit other mammalian cytochrome P450s

Question 13

Antifungal drugs: Azoles

• metabolized extensively by ___ cytochrome P450s
• All metabolites are inactive
• Only those azoles with ___ metabolism are used for systemic infection (7)

Answer 13

• liver
• reduced

1) Ketoconazole
2) Fluconazole
3) Itraconazole
4) Voriconazole
5) Posaconazole
6) Isavuconazole
7) Oteseconazole

Question 14

Ketoconazole

First azole with sufficient ___ bioavailability to be used clinically for deep tissue infections
- Based on miconazole
- Dioxolane ring on asymmetric carbon
- ___ metabolism by CYP3A

Answer 14

• oral
• Reduced

Question 15

Itraconazole

Based on ketoconazole
- ___ instead of imidazole
- Modified substituent on dioxolane ring
- Improved ___ for fungal P450 enzyme

Answer 15

• Triazole
• specificity

Question 16

Fluconazole

Substantially modified from ketoconazole
- ___ in place of imidazole
- __ in place of Cl on benzene ring
- Hydroxyl and 2nd triazole on asymmetric carbon
- ___ ring eliminated

Answer 16

• triazole
• F
• Dioxolane

Question 17

Voriconazole

Based on fluconazole
- Maintains triazole, hydroxyl, and fluorine substituents
- 2nd triazole replaced with ___ ring
- Added ___ group – improved binding to fungal ___ and increase spectrum

Answer 17

• fluoropyrimidine
• methyl, 14a-demethylase

Question 18

Posaconazole

Derived from itraconazole
- Has ___ ring – alters and increases spectrum of activity
- __ replaces Cl
- Broad spectrum activity
- Available for ___ (as suspension) and ___ admin

Answer 18

• furan
• F
• oral, IV

Question 19

Isavuconazole

Structurally similar to voriconazole
- Broad Spectrum

___ soluble
- ___ not required for solubility
- Reduced ___ relative to voriconazole

___ half life

Prodrug
- Cleaved by plasma ___
- very fast
- Release active drug and pro-drug cleavage product

Answer 19

• water, prodrug
• Cyclodextrin
• nephrotoxicity
• Long
• esterases

Question 20

Oteseconazole

• Used for high risk of fungal or yeast infections ( ___ )
• Improved treatment outcomes compared to ___
• Selective inhibition of the fungal enzyme CYP51 (a ___ )
• low number of AEs

Answer 20

• reoccurring
• fluconazole
• 14-a demethylase

Question 21

Azole drugs and CYP450

In general, azole antifungals are metabolized
by and inhibit ___ CYP450 enzymes
- ___ concentrations can be increased by other drugs metabolized by this pathway
- Concentration of drugs metabolized by CYP enzymes can be ___
- Inducers of CYPs, like ___ , can ___ triazole levels

Answer 21

• liver
• Triazole
• increased
• rifampin, decrease

Question 22

Azole drugs and CYP450

Ketoconazole is a potent ___ of CYP3A4

DIs:
- Increases area under curve and half life of ___
- Increases bioavailability of ___
- CYP3A4 inducers ( ___ , etc.) reduce ketoconazole levels

Answer 22

• inhibitor
• triazolam
• cyclosporin
• rifampin

Question 23

Azole metabolism

• Itraconazole - extensively metabolized by CYP3A4 in ___
• Fluconazole - 80 % excreted by kidney ___
• Voriconazole - metabolized extensively in liver by ___ > CYP3A4&raquo_space; CYP2C9 (polymorphisms can alter levels)
• Posaconazole - metabolized in liver by ___

Answer 23

• liver
• unchanged
• CYP2C19
• glucuronidation

Question 24

# Antifungal drugs: Echinocandins Lipopeptides - Synthetically modified fungal compounds - Caspofungin - Glarea lozoyensis - ___ - Coleophoma empetri - Anidulafungin - Aspergillus nidulans All must be administered by ___

Answer 24

Micafungin IV

Question 25

# Echinocandins Cyclic hexapeptides with long, modified ___ side chains

Answer 25

fatty acid

Question 26

# Echinocandins MOA: Inhibit synthesis of ___ - cell wall component - synthase is the target enzyme Reason for selectivity - ___ cells lack this activity Fungi ___ Broad Spectrum - Synergistic with ___ and ___ No cross resistance with other antifungals

Answer 26

- b(1-3)glucan - mammalian - fungicidal - voriconazole, amphotericin B

Question 27

# Echinocandins - clinical uses Caspofungin - Disseminated and mucocutaneous candida - Salvage therapy in patients with aspergillosis who fail to respond to ___ Micafungin - mucocutaneous candida - Candida prophylaxis in ___ ___ transplant patients Anidulafungin - ___ candidiasis - Invasive candidiasis - Has ___ half life and no known drug interactions Micafungin and anidulafungin are associated with fewer adverse events

Answer 27

- amphotericin B - bone marrow - Esophogeal - longest

Question 28

# Metabolism of echinocandins NOT metabolized by ___ - ___ and ___ generally have fewer adverse effects Degraded in blood and in tissues - Ring opening - Peptide hydrolysis

Answer 28

- liver CYPs - Anidulafungin, micafungin

Question 29

# Rezafungin - Novel, once- ___ echinocandin antifungal for adults with limited or no alternative treatment options (candidiasis) - IV administration, semisynthetic molecule that inhibits the ___ synthase enzyme. - Much ___ half-life (133 hours) than other echinocandins, which allowed for once-weekly dosing - Is being studied for invasive fungal diseases in blood and marrow transplants

Answer 29

- weekly - b-glucan - longer

Question 30

# Ibrexafungerp - small molecule inhibitor of ___ synthase enzyme in fungi - Triterpenoid antifungal that inhibits glucan synthase, depleting 1,3-b-D-glucan and acting as a ___ - Mostly active against candida and used for ___ candidiasis - Is metabolized by ___ by CYP3A4 and then via ___ and ___ - Well tolerated due to ___ activity against the glucan synthase enzyme.

Answer 30

- glucan - fungicidal - vulvovaginal - hydroxylation, glucuronidation, sulfation - selective

Question 31

# Antifungal drugs: flucytosine MOA: antimetabolite ( ___ analog) - inhibits ___ synthase - interferes with ___ sythesis Reason for specificity: mammalian cells are unable to convert flucytosine to active metabolite Synergizes with ___

Answer 31

- pyrimidine, - thymidylate - protein - amphotericin B

Question 32

# Flucytosine mechanism of action Flucytosine is first converted by cytosine deaminase to 5-fluorouracil - phosphorylated to form 5-FdUMP - 5-FdUMP mimics dUMP - 5-FdUMP is a substrate, a ___ inhibitor, and a ___ inhibitor of ___ synthase

Answer 32

- competitive, suicide, thymidylate

Question 33

# Flucytosine mechanism of action - In 5-FdUMP, there is a F in place of H found in dUMP - F is the most electronegative atom -> cannot be eliminated - ___ synthase trapped in an inactive form and cannot react with dUMP - No dTMP can be produced, and this inhibits ___ synthesis

Answer 33

- Thymidylate - DNA

Question 34

# Antifungal drugs: flucytosine Pharmacokinetics - Available only in ___ form - Penetrates well into all fluid compartments including ___ fluid - Removed by kidney - Renal impairment can lead to toxicity Adverse effects - Intestinal flora can metabolize to 5-FU - anti cancer drug - Monitor levels when combined with amphotericin B (why?)

Answer 34

- oral - cerebrospinal - synergistic

Question 35

# Clinical uses of flucytosine Limited spectrum of activity - Cryptococcus neoformans (Combined with ___ for cryptococcal meningitis) - Some Candida species - Aspergillus - Most filamentous fungi are not susceptible Narrow therapeutic window - too high: toxicity - too low: resistance Nearly always administered with ___ or ___

Answer 35

- amphotericin B - amphotericin B, fluconazole

Question 36

# Antifungal drugs: Griseofulvin - Produced by a strain of Penicillium - Disrupts fungal ___ - Fungi ___ - Must be given ___ - Becomes incorporated in keratin precursor cells - Used for dermatophytes ( ___ , ___ , and ___ ) - Inactive against yeast, mold, and dimorphic fungi

Answer 36

- microtubules - static - orally - skin, hair, and nails

Question 37

# Tavaborole MOA – inhibits ___ transfer ___ synthetase (LeuRS) - Inhibits ___ synthesis - ___ is essential for activity - ___ treatment of ___ (nail fungus)

Answer 37

- leucyl, RNA - protein - boron - onychomycosis

Question 38

# Resistance to antifungal agents Acquired resistance not transferred between strains as in bacteria Azoles - ___ site alteration – accounts for most resistant strains - Reduced drug concentration via efflux pumps - Target enzyme upregulation - Development of bypass pathways - Increasingly common, esp. Aspergillus Polyenes - reduced ___ content Echinocandins - target site mutations; rare Flucytosine - ___ deaminase or UPRT (cytosine permease) Allylamines and griseofulvin - not well characterized

Answer 38

- target - ergosterol - cytosine

Question 39

# Antifungal toxicity Hepatic (4) Renal (2) CNS and photopsia (1) Rash: all drugs Photosensitivity/malignancy (1) GI (3) Cardiomyopathy (1) GTc prolongation: all ___ Infusion reactions (2) Bone marrow suppression (2)

Answer 39

azoles

Question 40

# Antifungals during pregnancy ___ treatments OK ___ is treatment of choice for systemic infections azoles - avoid, especially in 1st trimester - possibility of birth defects and spontaneous abortion - Single dose of fluconazole 150 mg to treat vaginal yeast infection does not appear to be associated with the birth defects Voriconazole, flucytosine, and griseofulvin are ___ Not enough data on ___

Answer 40

- topical amphotericin - contraindicated - echinocandins