Antifungal Agents- Pharmacy-Medicinal Chemistry- As per PCI syllabus- Lecture Notes

1. ANTIFUNGAL AGENTS
Dr. Akhil Nagar
RCP-IPER
Shirpur

2. • Common fungi types invented in early years are
Trichophyton schoenleinii, C. Albicans.
• Collectively named as mycoses and homogeneous group of
fungi, the dermatophytes.
• These include ringworm, which are infections of the hair or
hair follicles, The causative microbes are specialized
saprophytes with the unusual ability to digest keratin.
• Systemic Mycoses: Diseases caused by the systemic
organisms include histoplasmosis, sporotrichosis,
blastomycosis, coccidioidomycosis, cryptococcosis, and
paracoccidioidomycosis.
• The causative agents for these diseases are saprophytes,
Fungal spores are inhaled into the lung, and a mild, cold like
condition may result.

3. Azole Antifungal Agents
• The azoles represent a class of synthetic antifungal agents that
possess a unique mechanism of action.
• selectivity for the infecting fungus
• one can treat infections ranging from simple dermatophytoses
to life-threatening, deep systemic fungal infections.
• Aimed at developing more potent azoles and compounds that
penetrate the blood-brain barrier more effectively.
• The first members of the class were highly substituted
imidazoles, such as clotrimazole and miconazole.
• Structure–activity studies revealed that the imidazole ring
could be replaced with a bioisosteric 1,2,4-triazole ring
without adversely affecting the antifungal properties of the
molecule.

4. • At high in vitro concentrations (micromolar), the azoles are
fungicidal; at low in vitro concentrations (nanomolar), they are
fungistatic.
• fungicidal effect is clearly associated with damage to the cell
membrane, with the loss of essential cellular components such
as potassium ions and amino acids.
• The fungistatic effect of the azoles at low concentration has
been associated with inhibition of membrane-bound enzymes.
• A cytochrome P450-class enzyme, lanosterol 14-demethylase,
is the likely target for the azoles.
• P450 possesses a heme moiety, The function of lanosterol 14-
demethylase is to oxidatively remove a methyl group from
lanosterol during ergosterol biosynthesis.
MECHANISM OF ACTION

6. There are three general mechanisms of action for the antifungal
agents:
1. Cell membrane disruption
2. Inhibition of cell division
3. Inhibition of cell wall formation. (Least)

7. Cell Membrane Disruption
• Antifungal agents that disrupt the cell membrane do so by
targeting ergosterol, either by binding to the sterol,
forming pores and causing the membrane to become leaky
or inhibiting ergosterol biosynthesis.
• Ergosterol is similar to mammalian cholesterol, thus
agents binding ergosterol may have a cytotoxic effect in
the host tissue. Ergosterol has two conjugated double
bonds that are lacking in mammalian sterols.

10. • When demethylation is inhibited, the 14-sterol accumulates
in the membrane, causing destabilization.
• Lanosterol 14-demethylase is also required for mammalian
biosynthesis of cholesterol and the azoles are known to
inhibit cholesterol biosynthesis.

11. • The 1,2,4-triazoles appear to cause a lower
incidence of endocrine effects and hepatotoxicity
than the corresponding imidazoles, possibly
because of a lower affinity for the mammalian
cytochrome P450 enzymes involved.
• The primary mode of resistance to the triazoles and
imidazoles in C. albicans is the development of
mutations in ERG 11, the gene coding for C14--
sterol demethylase.
• These mutations appear to protect heme in the
enzyme pocket from binding to azole but allow
access of the natural substrate of the enzyme,
lanosterol.

12. Clotrimazole
Econazole
Butoconazole

13. Oxiconazole
Tioconozole
Miconazole
1-[2-(2,4-Dichlorophenyl)-2-
[2,4-dichlorophenyl]-
methoxy]ethyl]-1H-imidazole
mononitrate

14. TerconazoleKetoconazole
Fluconazole

15. Naftifine hydrochloride
Tolnaftate
2-Naphthyl N-methyl-N-(3 tolyl)thionocarbamate[

16. STRUCTURE–ACTIVITY RELATIONSHIPS
• The basic structural requirement for members of the azole
class is a weakly basic imidazole or 1,2,4-triazole ring.
• (pKa of 6.5–6.8) bonded by a nitrogen–carbon linkage to the
rest of the structure.
• At the molecular level, the amidine nitrogen atom (N-3 in the
imidazoles, N-4 in the triazoles) is believed to bind to the heme
iron of enzyme-bound cytochrome P450 to inhibit activation of
molecular oxygen and prevent oxidation of steroidal substrates
by the enzyme.
• The most potent antifungal azoles possess two or three
aromatic rings, at least one of which is halogen substituted.
• (e.g., 2,4- dichlorophenyl, 4-chlorophenyl, 2,4-difluorophenyl),
and other nonpolar functional groups.

17. • Only 2, and/or 2,4 substitution yields effective azole
compounds.
• The halogen atom that yields the most potent compounds is
fluorine & sulfonic acids also gives same potency.
• The large nonpolar portion of these molecules mimics the
nonpolar steroidal part of the substrate for lanosterol 14-
demethylase, lanosterol, in shape and size.
• The nonpolar functionality confers high lipophilicity to the
antifungal azoles.
• The free bases are typically insoluble in water but are
soluble in most organic solvents, such as ethanol.
• Fluconazole, which possesses two polar triazole moieties, is
an exception, in that it is sufficiently water soluble to be
injected intravenously as a solution of the free base.