THE CHEMISTRY OF

ANTIFUNGAL AGENTS
MALINA JASAMAI
Faculty of Pharmacy, UKM.
malina@ukm.edu.my
 Background Knowledge
General structure of fungi (moulds & yeasts)
Asexual & sexual reproduction of fungi
Diseases caused by fungi & different type of
fungal infections in humans
 Learning outcomes
Describe the mode of action of antifungal agents
Discuss the structural modifications made to
produce better antifungal agents
List the different types of antifungal agents in the
market
References
Pharmaceutical Microbiology, Hugo, W.D.,
Russel, A.D. Blackwell Science
Principles of Medicinal Chemistry, Foye, W.O.
Lea & Febiger
An Introduction to Medicinal Chemistry,
Patrick, G.L. Oxford University Press.
 Introduction
Systemic infections
candidiasis, cryptococcosis meningitis,
aspergillosis, blastomycosis
 candidiasis
blastomycosis

cryptococcosis aspergillosis
 Fungal Diseases
Superficial infections
Tinea pedis, tinea corporis, tinea unguium
tinea pedis

tinea corporis

tinea unguium
 Possible Target

cholesterol ergosterol

• in a 3-dimensional model ring system, ergosterol is slightly

flatter
 Sterol biosynthesis in fungi

c-14 demethylase

HO HO
lanosterol

HO HO
ergosterol
 Azoles
The most important category of antifungals

IMIDAZOLES
Cl
N S
O O
N N N N N
Cl Cl Cl Cl

Cl
Cl Cl
clotrimazole miconazole tioconazole
 Azoles
TRIAZOLES
N
N
N Cl N F
N N
N
O HO N
O Cl F N F
N
O N F
N OH N N
N fluconazole
N
O F
Itraconazole N voriconazole
N
N
Mode of Action
O

N
N

O
O Cl
O

N
+
N
N Cl
N Fe N
N

14 alpha-demethylase haem
 Mode of Action
Inhibit cytochrome P-450 which catalyses the 1,4-
demethylation of lanosterol
- CP-450 carries out oxidative removal of the 14-methyl
of lanosterol
The azoles complex to the iron atom of the CP-450
preventing substrate binding
Leads to the accumulation of the 14-! methyl sterols
which do not have the exact shape & physical
properties of the normal membrane ergosterol
- permeability changes, leaky membranes & malfuction
membrane-imbedded proteins cell death
 Selectivity
IC50 value different from human
Human cells contain sterol C-24 demethylase which
involved in the biosynthesis of cholesterol
- different binding pockets of the human & fungal
enzymes
However the azoles (esp ketaconazole) also inhibit other
CP-450 iso enzymes (hydroxylases, lyases & aromatase)
TOXICITY
 Discovery of Fluconazole
Imidazoles show very good activity when applied topically
Diminished activity when given orally or iv
- susceptible to metabolic inactivation
- very lipophilic bind to plasma protein (low plasma
O
level of drugs)
Ketoconazole, an improvement N
- less metabolic instability N
- less lipophilic
(higher plasma level of drugs) O O
O Cl

N
N
Cl
 Discovery of Fluconazole
Reduced lipophilicity (introduce polar groups)
Improved stability (triazole ring)
Reduced toxicity

N N
N F
N
N
VS HO
F
Cl N
N
N
clotrimazole flluconazole
Polyene Membrane Disrupters
 Polyene Membrane Disrupters
o Have affinity for sterol containing membrane
o insert into membranes & disrupt membrane functions
o cell become leaky
o loss esssential cell constituents (ions, organic molecules)
o cell death
o nystatin, amphotericin B, natamycin
Other Antifungal Agents in the
Market
Other Antifungal Agents in the
Market
Other Antifungal Agents in the
Market