Lecture 8 - Antifungals Flashcards
What are the types of antifungal?
topical (nails, hair or skin)
oral
intravenous
intravaginal antifungal pessaries (small soft tabs)
What are the structural classes of antifungals?
polyenes
azoles (imidazole, triazoles)
echinocandins
allylamines
others
Structure of polyenes?
large, complicated molecules which consist of a number of unsaturations (alkenes)
Examples of polyenes?
amphotericin B (fungizone, ambisome, amphocil (POMs))
nystatin (nystan - POM)
Examples of imidazoles?
clotrimazole, miconazole, ketoconazole, econazole
Nizoral?
ketoconazole
POM
Canesten?
clotrimazole
Daktarin?
miconazole
Ecostatin, pevaryl?
Econazole
Structure of imidazoles?
all have the benzene ring with 2 nitrogens (imidazole ring)
Examples of triazoles?
fluconazole
voriconazole
itraconazole
posaconazole
Diflucan?
fluconazole POM
Vfend?
voriconazole POM
Sporanox?
itraconazole POM
Noxafil?
posaconazole POM
Triazole ring?
three nitrogens in heterocyclic ring
Echinocandins?
caspofungin
cancidas - POM
Echinocandins structure?
complicated molecule with lots of chiral centres
Allylamines?
terbinafine (lamisil - POM)
Other antifugals?
griseofulvin
flucytosine
What is grisefulvin from?
penicillium grisesfulvum
Ancotil & valeant?
flucytosine (POM)
How do polyenes work?
bind directly with ergosterol in the cell membrane, causing leakage and cell death
How do azoles work?
competitively inhibits the lanosterol
14alpha-demethylase (P45014DM, CYP51) enzyme involved in ergosteroil biosynthesis
How do echinocandins work?
non-competitively inhibit beta-1-3-D-glucan biosynthesis in cell wall causing cell lysis and death
How do allylamines work?
Inhibit squalene epoxidase required for ergosterol biosynthesis
How does griseofulvin work?
binds to polymerised microtubules in nucleus and prevents mitosis
How does flucytosine work?
an antimetabolite which interferes with RNA and DNA synthesis in the cell nucleus causing cell death
What is the genomic based approach for drug development?
1) target ID & validation
2) assay development
3) HTS (>60% inhibition), virtual and fragment screening
4) ligand optimisation
What is the phenotypic approach?
CLASSIC approach
synthetic libraries
natural product libraries
hypothesis drive
re-purposing of old drugs
What was the starting point of the imidazoles?
the imidazole containing metronidazole which had broad antibacterial activity
What is metronidazole a derivative of?
azomycin
What did further iterations of miconazole lead to?
clotrimazole and miconazole
What was found to be important for activity in imidazoles?
the dioxolane ring
What did even further iterations develop?
ketoconazole
What isomer is better?
cis isomer is better than trans
when a dash becomes a wedge
What is the imidazole ring sensitive to?
metabolism in the liver, which caused toxicity
What was imidazole replaced with?
triazole
metabolically more stable and safer
What triazoles did iterations first lead to?
itraconazole and posaconazole
What was wrong with itraconazole and posaconazole?
they have high log P values and bound to blood plasma proteins, causing low bioavailability
What was developed after further iterations and what was better about this?
fluconazole
had a lower log P, lower MWt
What is the pharmacophore?
it is the area required for activity and needs to bond with the active site
What do pi-pi interactions occur between?
benzene rings
What happens if we remove key interactions of a drug with the active site?
a higher concentration is needed to kill and inhibit the enzyme
What does the structure of a drug affect?
the activity at the target and the spectrum of activity
What do drugs need to get to?
the target and then get metabolised
