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Management of Infection > Lecture 8 - Antifungals > Flashcards

Lecture 8 - Antifungals Flashcards

1
Q

What are the types of antifungal?

A

topical (nails, hair or skin)

oral

intravenous

intravaginal antifungal pessaries (small soft tabs)

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2
Q

What are the structural classes of antifungals?

A

polyenes

azoles (imidazole, triazoles)

echinocandins

allylamines

others

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3
Q

Structure of polyenes?

A

large, complicated molecules which consist of a number of unsaturations (alkenes)

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4
Q

Examples of polyenes?

A

amphotericin B (fungizone, ambisome, amphocil (POMs))

nystatin (nystan - POM)

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5
Q

Examples of imidazoles?

A

clotrimazole, miconazole, ketoconazole, econazole

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6
Q

Nizoral?

A

ketoconazole

POM

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7
Q

Canesten?

A

clotrimazole

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8
Q

Daktarin?

A

miconazole

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9
Q

Ecostatin, pevaryl?

A

Econazole

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10
Q

Structure of imidazoles?

A

all have the benzene ring with 2 nitrogens (imidazole ring)

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11
Q

Examples of triazoles?

A

fluconazole

voriconazole

itraconazole

posaconazole

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12
Q

Diflucan?

A

fluconazole POM

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13
Q

Vfend?

A

voriconazole POM

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14
Q

Sporanox?

A

itraconazole POM

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15
Q

Noxafil?

A

posaconazole POM

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16
Q

Triazole ring?

A

three nitrogens in heterocyclic ring

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17
Q

Echinocandins?

A

caspofungin

cancidas - POM

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18
Q

Echinocandins structure?

A

complicated molecule with lots of chiral centres

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19
Q

Allylamines?

A

terbinafine (lamisil - POM)

20
Q

Other antifugals?

A

griseofulvin

flucytosine

21
Q

What is grisefulvin from?

A

penicillium grisesfulvum

22
Q

Ancotil & valeant?

A

flucytosine (POM)

23
Q

How do polyenes work?

A

bind directly with ergosterol in the cell membrane, causing leakage and cell death

24
Q

How do azoles work?

A

competitively inhibits the lanosterol

14alpha-demethylase (P45014DM, CYP51) enzyme involved in ergosteroil biosynthesis

25
Q

How do echinocandins work?

A

non-competitively inhibit beta-1-3-D-glucan biosynthesis in cell wall causing cell lysis and death

26
Q

How do allylamines work?

A

Inhibit squalene epoxidase required for ergosterol biosynthesis

27
Q

How does griseofulvin work?

A

binds to polymerised microtubules in nucleus and prevents mitosis

28
Q

How does flucytosine work?

A

an antimetabolite which interferes with RNA and DNA synthesis in the cell nucleus causing cell death

29
Q

What is the genomic based approach for drug development?

A

1) target ID & validation
2) assay development
3) HTS (>60% inhibition), virtual and fragment screening
4) ligand optimisation

30
Q

What is the phenotypic approach?

A

CLASSIC approach
synthetic libraries

natural product libraries

hypothesis drive

re-purposing of old drugs

31
Q

What was the starting point of the imidazoles?

A

the imidazole containing metronidazole which had broad antibacterial activity

32
Q

What is metronidazole a derivative of?

A

azomycin

33
Q

What did further iterations of miconazole lead to?

A

clotrimazole and miconazole

34
Q

What was found to be important for activity in imidazoles?

A

the dioxolane ring

35
Q

What did even further iterations develop?

A

ketoconazole

36
Q

What isomer is better?

A

cis isomer is better than trans

when a dash becomes a wedge

37
Q

What is the imidazole ring sensitive to?

A

metabolism in the liver, which caused toxicity

38
Q

What was imidazole replaced with?

A

triazole

metabolically more stable and safer

39
Q

What triazoles did iterations first lead to?

A

itraconazole and posaconazole

40
Q

What was wrong with itraconazole and posaconazole?

A

they have high log P values and bound to blood plasma proteins, causing low bioavailability

41
Q

What was developed after further iterations and what was better about this?

A

fluconazole

had a lower log P, lower MWt

42
Q

What is the pharmacophore?

A

it is the area required for activity and needs to bond with the active site

43
Q

What do pi-pi interactions occur between?

A

benzene rings

44
Q

What happens if we remove key interactions of a drug with the active site?

A

a higher concentration is needed to kill and inhibit the enzyme

45
Q

What does the structure of a drug affect?

A

the activity at the target and the spectrum of activity

46
Q

What do drugs need to get to?

A

the target and then get metabolised

Management of Infection (36 decks)

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