Lecture 8 - Antifungals

Question 1

What are the types of antifungal?

Answer 1

topical (nails, hair or skin)

oral

intravenous

intravaginal antifungal pessaries (small soft tabs)

Question 2

What are the structural classes of antifungals?

Answer 2

polyenes

azoles (imidazole, triazoles)

echinocandins

allylamines

others

Question 3

Structure of polyenes?

Answer 3

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

Question 4

Examples of polyenes?

Answer 4

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

nystatin (nystan - POM)

Question 5

Examples of imidazoles?

Answer 5

clotrimazole, miconazole, ketoconazole, econazole

Question 6

Nizoral?

Answer 6

ketoconazole

POM

Question 7

Canesten?

Answer 7

clotrimazole

Question 8

Daktarin?

Answer 8

miconazole

Question 9

Ecostatin, pevaryl?

Answer 9

Econazole

Question 10

Structure of imidazoles?

Answer 10

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

Question 11

Examples of triazoles?

Answer 11

fluconazole

voriconazole

itraconazole

posaconazole

Question 12

Diflucan?

Answer 12

fluconazole POM

Question 13

Vfend?

Answer 13

voriconazole POM

Question 14

Sporanox?

Answer 14

itraconazole POM

Question 15

Noxafil?

Answer 15

posaconazole POM

Question 16

Triazole ring?

Answer 16

three nitrogens in heterocyclic ring

Question 17

Echinocandins?

Answer 17

caspofungin

cancidas - POM

Question 18

Echinocandins structure?

Answer 18

complicated molecule with lots of chiral centres

Question 19

Allylamines?

Answer 19

terbinafine (lamisil - POM)

Question 20

Other antifugals?

Answer 20

griseofulvin

flucytosine

Question 21

What is grisefulvin from?

Answer 21

penicillium grisesfulvum

Question 22

Ancotil & valeant?

Answer 22

flucytosine (POM)

Question 23

How do polyenes work?

Answer 23

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

Question 24

How do azoles work?

Answer 24

competitively inhibits the lanosterol

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

Question 25

How do echinocandins work?

Answer 25

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

Question 26

How do allylamines work?

Answer 26

Inhibit squalene epoxidase required for ergosterol biosynthesis

Question 27

How does griseofulvin work?

Answer 27

binds to polymerised microtubules in nucleus and prevents mitosis

Question 28

How does flucytosine work?

Answer 28

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

Question 29

What is the genomic based approach for drug development?

Answer 29

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

Question 30

What is the phenotypic approach?

Answer 30

CLASSIC approach synthetic libraries natural product libraries hypothesis drive re-purposing of old drugs

Question 31

What was the starting point of the imidazoles?

Answer 31

the imidazole containing metronidazole which had broad antibacterial activity

Question 32

What is metronidazole a derivative of?

Answer 32

azomycin

Question 33

What did further iterations of miconazole lead to?

Answer 33

clotrimazole and miconazole

Question 34

What was found to be important for activity in imidazoles?

Answer 34

the dioxolane ring

Question 35

What did even further iterations develop?

Answer 35

ketoconazole

Question 36

What isomer is better?

Answer 36

cis isomer is better than trans | when a dash becomes a wedge

Question 37

What is the imidazole ring sensitive to?

Answer 37

metabolism in the liver, which caused toxicity

Question 38

What was imidazole replaced with?

Answer 38

triazole metabolically more stable and safer

Question 39

What triazoles did iterations first lead to?

Answer 39

itraconazole and posaconazole

Question 40

What was wrong with itraconazole and posaconazole?

Answer 40

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

Question 41

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

Answer 41

fluconazole had a lower log P, lower MWt

Question 42

What is the pharmacophore?

Answer 42

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

Question 43

What do pi-pi interactions occur between?

Answer 43

benzene rings

Question 44

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

Answer 44

a higher concentration is needed to kill and inhibit the enzyme

Question 45

What does the structure of a drug affect?

Answer 45

the activity at the target and the spectrum of activity

Question 46

What do drugs need to get to?

Answer 46

the target and then get metabolised