This document discusses various types of fungi and fungal infections. It begins by describing the characteristics of fungi, including their cell structure and cell wall composition. It then classifies fungi and describes the types of infections they can cause, including superficial, subcutaneous, systemic, and opportunistic infections. Specific fungal genera and species that cause different types of infections are identified. The document also categorizes and describes various classes of antifungal drugs, including their mechanisms of action, pharmacokinetics, therapeutic uses, and adverse effects. These drug classes include azoles, polyenes like amphotericin B, and echinocandins.

1. “Teaching Pedagogy in Medicinal Chemistry at
Post-Graduate level”
10-12-2016
ANTIFUNGALs
Dr. (Mrs.) Sangeeta Vijay Jagtap
Associate Professor
Baburaoji Gholap College, Sangvi, Pune

3. FUNGI
• Fungi are eukaryotic cells and as such contain nuclei,
mitochondria, ER, golgi, 80S ribosomes, etc., bound bya plasma
membrane.
• The fungal kingdom includes yeasts, molds, rusts and
mushrooms. In general most fungi are beneficial and are involved
in biodegradation. A few can cause opportunistic infections if they
are introduced into a human through wounds or by inhalation.
• The importance of fungi as pathogens is increasing due to aging
population, HIV, immunosuppression in organ transplant and
unknown factors.
•Fungi possess a rigid cell wall containing chitin, glucans and other
sugar polymers. Arrangement of the biomolecular components of
the cell wall accounts for the individual identity of the organism.
Although, each organism has a different biochemical composition,
their gross cell wall structure is similar.
• Fungal cell wall differs greatly from bacterial cell wall. Therefore,
fungi are unaffected by antibacterial cell wall inhibitors such as -
lactams and vancomycins.

4. Classification of Fungi
Fungi are classified as
•Yeasts - round/oval cells that divide
by budding. (e.g. Candida,
Cryptococcus neoformans )
•Molds - tubular structures (hyphae)
that grow by longitudinal extension
and branching. A mass of hyphae is
called a mycelium. (Aspergillus)
Dimorphic have growth characteristics of both. At body temperature,
they grow as yeast in host tissues; whereas at ambient temperature
they grow as molds in saprophytes

5. Infections caused by Fungi
Fungal infections are classified depending on the
degree of tissue involvement and mode of entry:
1. Superficial - localized to the skin, hair and nails.
2. Subcutaneous - infection confined to the dermis,
subcutaneous tissue, or adjacent structures.
3. Systemic - deep infections of the internal organs.
4. Opportunistic - cause infection only in the
immunocompromised (AIDS, chemotherapy,
post-surgery).

6. Superficial
The Dermatophytes
Superficial infections are caused by a variety of fungi, especially
the dermatophytes (causing infection of the skin, hair and nails)
belonging to 40 related fungi of three genera: Microsporum,
Trichophyton, Epidermophyton. Dermatophytic infections known
as Tinea and are named for the site of infection rather than the
causative organism.
Tinea pedis
“athletes foot”
Epidermophyt
on spp.
Tinea capitis
Microsporum
spp.
Tinea corporis
Ringworm, dermatophyte
infection (zoophilic)

7. Subcutaneous
Subcutaneous infections are confined to the
dermis, subcutaneous tissue, or adjacent
structures; there is no systemic spread.
They tend to be slow in onset and chronic in
duration.
These mycoses are rare in the US and are
primarily confined to tropical regions (the
Americas, South Africa, Australia).
Variety of fungi involved. Infection starts with
trauma inoculation from soil or plants.
Lobomycosis

8. Systemic
Systemic mycoses are invasive infections of the internal
organs.
The organism typically gains entry via the lungs, GI tract,
or through intravenous lines.
Examples include:
•Histoplasmosis - Histoplasmosis is caused by
Histoplasma, a dimorphic fungus
•Coccidiomycosis - An infection caused by the
dimorphic fungus, Coccidioides immitis.
•Blastomycosis - A disease caused by the dimorphic,
fungus Blastomyces dermatitidis
Discoloration of the
skin caused by
Histoplasma
capsulatum
The lesion on the
Nose Resulted From
dissemination
From the lungs
Skin lesion following
dissemination from
the lungs

9. Opportunistic fungi are normally of marginal pathogenicity, but can
infect the immunocompromised host.
Patients usually have some serious immune or metabolic defect,
or have undergone surgery.
Examples include:
Candidiasis - an infection caused by a Candida spp.
Aspergillosis is a large spectrum of diseases caused by
members of the genus Aspergillus.
Cryptococcus is an encapsulated yeast found world-wide; it is
found in pigeon droppings, eucalyptus trees, some fruits and
contaminated milk.
Opportunistic
Oral Thrush- the white
material consists of
budding yeast cells and
pseudohyphae.
Fruiting body in
a lung cavity
Skin lesions
resulting from
disseminated
C. neoformans

10. Classification of Antifungal Drugs
A. According to Mechanism of action
1. Drugs affecting synthesis / Functions of cell membrane
i. Synthesis (inhibit synthesis of ergosterol)
- Ketoconazole, Fluconazole, traconazole,
Voviconazole, Miconazole, Turbenafine (inhibit
enzyme squaline epoxide so interfere ergosterol
synthesis)
ii. Function
Polyene antibiotics = Amphotericin B, Nystatin
2. Block nucleic acid synthsis
- Flucytosine
3. Distrupts microtubular function
- Griseofulvin
4. Reduction of fungal cell wall viability
- Pradimicin, Nikkomycin
5. Fungal protein synthesis inhibitor
-Jordanians

11. B. According to route of administration :
1. Topical
Nystatin, Clotrimazole, Econazole, Amphotericin-B
2. Oral
Miconazole, Ketoconazole, Fluconazole, Itraconazole,
Flucytosine, Grisofulvin, Terbenafine
3. Intravenous
Amphotericin, Miconazole, Fluconazole, Flucytosine

12. C. According to Therapeutic action :
1. Superficial
i. Dermatophytes (ringworms)
- Griseofulvin, Terbanafine, Ketoconazole, Nystatin
ii. Candidacies
- Fluconazole, Miconazole
2. Systemic
i. Ketoconazole
- Histoplassm, Blastomycosis
ii. Ketoconazole
- cocciciodomy, para
iii. Amphotericin B cocdiodo
- Cryptococcus, Candidacies, zygomycosis
iv. Fluconazole
- candidiasis
v. Flucytosine
- candidiasis, Cryptococcus

13. D. According to Chemical /structure :

14. Antibiotic Antifungal Drugs
 Polyenes: Amphotericin B, Nystatin

15. Amphotericin B
 Produced by Streptomyces nodosus.
Amphoteric polyene macrolide.
Chemistry
-Amphotericin B is a polyene antibiotic
(polyene: containing many double bonds)

17. Mechanism of action
-Binding to ergosterol present in the membranes of fungal cells

Formation of “pores” in the membrane

Leaking of small molecules (mainly K+) from the cells
-The ultimate effect may be fungicidal or fungistatic
depending on the organism and on drug concentration.
Pharmacological Effect: broad-spectrum
Mechanism: binds to ergosterol in fungi (cholesterol in
humans and bacteria) to form pores

18.  Pharmacokinetics:
◦ Poorly absorbed from the gastrointestinal tract.
◦ More than 90% bound by serum proteins.
◦ Metabolized in liver, excreted slowly in the
urine.
 Adverse Effects:
◦ Infusion-Related Toxicity: fever, chills, muscle
spasms, vomiting, headache, hypotension.
◦ Slower Toxicity:
 Renal toxicity
 K+↓, Mg2+↓
 Anemia: due to erythropoietin ↓
 Abnormalities of liver function
 Neurologic sequelae (Neurological symptoms
like convulsions, seizures)

19. Pharmacokinetics
-f(oral): < 1% (too irritant to be given IM) (f=Bioavailibility)
-Distribution in all body tissues, except CNS and eye
(concentrations in CSF are <10% than in plasma; however
therapeutic concentrations in CNS can usually be achieved with
parenteral administration)
-Biotransformation: > 95%
-Renal excretion: < 5%
-Half life: » 14 days
Drug formulations and administration
-Formulations:
a) complex with deoxycholate
b) liposomal complex (adverse effects seem diminished)
-Administration:
IV infusion, intrathecal, topical, oral (to treat intestinal mycoses)

20. Adverse effects
(the therapeutic index of the drug is very narrow)
-Headache, arthralgias, nausea and vomiting fever with
chills, hyperpnea (increased rate of respiration),
shock-like features like tachycardia and hypotension
-Malaise (Muscle pain), weight loss
-Nephrotoxicity (azotemia , decreased GFR, renal
tubular acidosis, renal wasting of K+ and Mg++,). It
is common (up to 80% of patients) and may be
severe
-Normocytic anemia, likely due to decreased production
of erythropoietin (frequent)
-Thrombophlebitis
-Delirium, seizures (after intrathecal injection)

21. Therapeutic uses:
used for deep and superficial infections
Amphotericin is the drug of choice for:
-Disseminated histoplasmosis
-Disseminated and meningeal coccidioidomycosis
-Disseminated and meningeal cryptococcosis
-Invasive aspergillosis
-Deep candidiasis
-Mucormycosis
Amphotericin is an alternative drug for:
-Blastomycosis (fungal infection of humans and other animals, notably dogs and occasionally
cats)
-Paracoccidioidomycosis
-Extracutaneous sporotrichosis
[Amphotericin is preferred when these mycoses are rapidly
progressive, occur in immunocompromised host or
involve the CNS]

22. Azoles
 Synthetic compounds.
 Classification: according to the
number of nitrogen atoms in the
five-membered azole ring
◦ Imidazoles: Ketoconazole, Miconazole,
Econazole, Clotrimazole, Bifonazole
◦ Triazoles: Itraconazole, Fluconazol,
Vorionazole → systemic treatment

24. Mechanism of Action
 Reduction of ergosterol synthesis by
inhibition of fungal cytochrome P450
enzymes.
 Greater affinity for fungal than for
human cytochrome P450 enzymes.
 Imidazoles exhibit a lesser degree of
specificity than the triazoles, accounting
for their higher incidence of drug
interactions and side effects.

25. Ketoconazole
 The first oral azole introduced into
clinical use.
 Less selective for fungal P450
◦ Inhibition of human P450 interferes with
biosynthesis of adrenal and gonadal steroid
hormones;
◦ Alter the metabolism of other drugs.
 Best absorbed at a low gastric pH.

27. Miconazole, Econazole, Clotrimazole
 Bioavailability is low by taking orally.
 Used topically.
Bifonazole
 Double inhibition, antifungal action is more
powerful.
Itraconazole
 Its absorption is increased by food and by low
gastric pH.
 Treatment of dermatophytoses and
onychomycosis .
 The only agent with significant activity against
aspergillus species.

28. Fluconazole
 Water solubility and good cerebrospinal fluid
penetration.
 The widest therapeutic index of the azoles (broad
spectrum).
 Treatment and secondary prophylaxis of
cryptococcal meningitis .
Vorionazole
 Available in an intreavenous and an oral
formulation.
 Metabolism is predominantly hepatic, but the
propensity for inhibition of mammalian P450
appears to be low.
 Similar to itraconazole in this spectrum of action,
having good activity against candida species.
 More effective than itraconazole.

29. PHARMACOLOGY OF ANTIFUNGAL AZOLES
Chemistry
-Imidazole derivatives: ketoconazole, miconazole, econazole,
clotrimazole
-Triazole derivatives: itraconazole, fluconazole.
Mechanism of action
-Inhibition of sterol 14-alpha-demethylase, a cytochrome P450-
dependent enzyme (relative selectivity occurs because the
affinity for mammalian P450 isozymes is less than that for the
fungal isozyme)

blockade of the synthesis of ergosterol in fungal cell
membranes
-The ultimate effect may be fungicidal or fungistatic depending
on the organism and on drug concentration.

30. Pharmacologic properties of five systemic
azole drugs
Water
Solubility
Absorption CSF: Serum
Concentration
Ratio
t 1/2
(Hours)
Elimination Formulations
Ketoconazole Low Variable < 0.1 7–10 Hepatic Oral
Itraconazole Low Variable < 0.01 24–42 Hepatic Oral, IV
Fluconazole High High > 0.7 22–31 Renal Oral, IV
Voriconazole High High . . . 6 Hepatic Oral, IV
Posaconazole Low High . . . 25 Hepatic Oral

31. Pharmacokinetics and administration
-F(oral): itraconazole » 55%, fluconazole >90%.
(acidity favors oral absorption of ketoconazole)
-Distribution in all body tissues. Penetration into CNS is generally
negligible, but good for fluconazole.
-Renal excretion: fluconazole » 75%, others < 1%
-Half-lives (hrs): ketoconazole » 8, itraconazole » 35
-Administration: oral, IV, topical
Adverse effects
-Anorexia (lack or loss of appetite for food, thereby loss of weight), nausea and
vomiting (they are dose-dependent and patients receiving high
doses may require antiemetics)
-Gynecomastia, decreased libido, impotence, menstrual
irregularities (with ketoconazole, due to blockade of adrenal
steroid synthesis)
-Hepatitis (is rare, but can be fatal)
-Hypokalemia, hypertension (itraconazole)
-Azoles are potent teratogenic drugs in animals

32. Therapeutic uses
Azoles are first choice drugs for:
-Blastomycosis (ketoconazole)
-Paracoccidioidomycosis (ketoconazole)
-Chronic pulmonary histoplasmosis
-Meningeal coccidioidomycosis (fluconazole)
-Meningeal cryptococcosis (fluconazole)
-Cutaneous and deep candidiasis
Azoles are alternative drug for:
-Invasive aspergillosis
-Sporotrichosis
Topical azoles are used for:
-Dermatophytoses (not of hair and nails)
-Tinea versicolor
-Mucocutaneous candidiasis
Contraindications
-Systemic azoles are contraindicated in pregnancy (potential
teratogenic effects and endocrine toxicity for the fetus)

33. β-Glucan Synthetase inhibitor
(Echinocandins)
 Newest class of antifungal agents
 Intravenous
 inhibiting the synthesis of (1–3)-glucan
 Well tolerated
 Caspofungin
 Micafungin
 Anidulafungin

34. Pharmacokinetics and administration
-f(oral): » 50% (micronization of the drug and a high-fat food favor oral
absorption)
-Distribution is mainly in keratinized tissues where the drug is
tightly bound and where it can be detected 4-8 hours after oral
administration. Concentration in other tissues and body fluids is
negligible.
-Elimination: mainly in the feces.
-Half-life (hrs): » 24 hours
-Administration: oral
Adverse effects
(incidence is quite low)
-Xerostomia, nausea and vomiting, diarrhea
-Headache (up to 15%), fatigue, blurred vision, vertigo, increased
effects of alcohol
-Hepatotoxicity (rare)
-Leukopenia, neutropenia
-Allergic reactions (urticaria, skin rashes, serum sickness, angioedema)
-Teratogenic effects in several animal species
Therapeutic uses
-Mycotic disease of the skin, hair and nails (long treatments are
needed)

35. TOPICAL ANTIFUNGAL DRUGS
Nystatin
-A polyene antibiotic useful only for local candidiasis.
-Administration: cutaneous, vaginal, oral.
Haloprogin
-The drug is fungicidal to various species of dermatophytes and candida.
-Principal use: in tinea pedis (cure rate » 80% )
Tolnaftate
-The drug is effective against most dermatophytes and Malassezia furfur but
not against Candida
-In tinea pedis the cure rate is » 80%
Antifungal azoles
-Azoles are reported to cure dermatophyte infections in 60-100% of cases
-The cure rate of mucocutaneous candidiasis is > 80% and that of tinea
versicolor > 90%.
-Administration: cutaneous, vaginal.
-Cutaneous application rarely causes erythema, edema, vescication,
desquamation and urticaria
-Vaginal application may cause mild burning sensation and abdominal pain.

37. Allylamine
 Include Naftifine and Terbinafine.
 non-competitive and reversible inhibitor
of Squalene epoxidase.
 Terbinafine is synthetic, oral formulation.
◦ Fungicidal
◦ Treatment of dermatophytoses, especially
onychomycosis, more effective than
griseofulvin or itraconazole.

39. Griseofulvin
 Derived from a species
of penicillium.
 Fungistatic drug.
 Insoluble.
 Administered in a microcrystalline
form only using in the systemic
treatment of dermatophytosis .
 Deposited in newly forming skin
where it binds to keratin, protecting
the skin from new infection.
Non-polyenes:

40. PHARMACOLOGY OF GRISEOFULVIN
Chemistry
-Griseofulvin is a benzofuran derivative
-The drug is practically insoluble in water
Mechanism of action
-An active transport accumulates the drug in sensitive fungal
cells where

griseofulvin causes disruption of the mitotic spindle by interacting
with polymerized mycrotubules
-The ultimate effect is fungistatic
Antifungal spectrum and resistance
-Antifungal spectrum includes only Dermatophytes
(Microsporum, Epidermophyton, Trichophyton)
-The drug is ineffective against other fungi producing superficial
lesions (like Candida and Malassezia furfur) and those producing
deep mycoses.
-Resistance is uncommon. It seems to be due to a decrease of
the energy-dependent transport mechanism.

41. Pyrimidine derivatives
 Flucytosine （5-FC）is a water-soluble
pyrimidine analog.
 Its spectrum of action is much narrower
than that of amphotericin B.
 Poorly protein-bound and penetrates
well into all body fluid aompartments,
including the cerebrospinal fluid.
Flucytosine Fluorouracil

42.  Mechanism
◦ 5-FC (taken up by fungal cells via the enzyme
cytosine permease) → 5-FU → F-dUMP and FUTP
→ inhibit DNA and RNA synthesis, respectively.
 Synergy with amphotericin B.
 Spectrum of action: Cryptococcus
neoformans, some candida species, and the
dematiaceous molds that cause
chromoblastomycosis.

44.  Not used as a single agent because of its
demonstrated synergy with other agents
and to avoid the development of
secondary resistance.
 Adverse effects: result from metabolism
to fluorouracil (5-FU)
◦ Bone marrow toxicity with anemia, leukopenia,
and thrombocytopenia

45. PHARMACOLOGY OF FLUCYTOSINE
Chemistry : Flucytosine is a fluorinated pyrimidine
Mechanism of action
-The drug is accumulated in fungal cells by the action of a
membrane permease and is converted by a cytosine
deaminase to 5-fluorouracil (selectivity occurs because
mammalian cells do not accumulate and do not deaminate
flucytosine)

5-fluorouracil is metabolized to 5-fluorouridylic acid which can be
a) incorporated into the RNA (this leads to a misreading of the
fungal genetic code)
b) further metabolized to 5-deoxyfluorouridylic acid, a potent
inhibitor of thymidylate synthase (this leads to a blockade of
fungal DNA synthesis)
-The ultimate effect may be fungicidal or fungistatic depending
on the organism and on drug concentration.

46. Pharmacokinetics and administration
-F(oral): > 80%
-Distribution in all body tissues, including CNS and
the eye.
-Volume of distribution: » 42 L
-Renal excretion: » 99%
-Half-life: » 4 hours (in renal failure, half-life may be
as long as 200 hours)
-Administration: oral, IV

47. Adverse effects
(toxicity is generally not pronounced)
-Anorexia (Weight loss), nausea and vomiting, diarrhea
-Severe ulcerative enterocolitis (rare)
-Skin rashes
-Headache, dizziness, confusion
-Reversible bone marrow depression (8-13%)(leukopenia,
thrombocytopenia)
-Liver dysfunction (5-10%)
-Alopecia, peripheral neuritis (rare)
[toxicity may be due to the conversion of flucytosine to 5-
fluorouracil by the intestinal flora of the host]
Therapeutic uses
-Deep candida infections, cryptococcal meningitidis (always in
combination with amphotericin B)
-Chromomycosis (effectiveness is limited)
Contraindications
-Pregnancy ( 5-fluorouracil is teratogenic (harmfull to the foetus))

48. Targets of antifungal drugs