ANTIFUNGAL AGENTS

TWO (2) TYPES of FUNGAL INFECTIONS:

1. SUPERFICIAL MYCOSES (skin & nails) - caused by dermatophytes these
includes Tinea infections
affecting hair or hair follicles, flat areas of hairless skin and infection of the nails -
> incidence rate is high.
o Causative microbes are saprophytes with unusual ability to digest keratin

a. Dermatophytes- homogeneous group of fungi (e.g.

tinea/ringworm)
b. Specialized Saprophytes (keratin-digesting fungi)

CUTANEOUS INFECTIONS (dermatophytoses) - cause

infections of the skin by dermatophytes in the
Microsporum, Trichophyton or Epidermophyton genera. These
dermophytic infections are named for
the site of infection rather than the causative organism.

SUBCUTANEOUS F.I.
- refers to a group of fungal disease which both the skin and subcutaneous tissues are involved
(internal organs are not affected)
-skin+subcutaneous tissues but do not involve internal organs
Characteristics:
a. Soil saprophytes of very low grade virulence and invasive ability and they gain access as a result
of trauma to the tissue.
b. In most human and animal infections, they gain acces as a result of a trauma to the tissue.
THE MAJOR DISEASE TYPES ARE: chromomycosis, sporotrichosis, mycetoma, lobomycosis and
entomophthoromycosis.

2. DEEP-SEATED MYCOSES (DSM)

-are transmitted from one host to another (e.g. yeast spp)
*SYSTEMIC MYCOSES “true pathogens”
-is under DSM, involves heterogeneous group of fungi
-saprophytes that are soil-inhabiting
*OPPURTUNISTIC F.I.
-due to immunosuppressive agents cytotoxins, irradiation, and steroids, a new category of systematic
mycoses has become prominent.
- opportunistic fungal infections

ANTIFUNGAL should be ‘SELECTIVE TOXICITY’ in order not to harm the host

Sterol- steroid alcohol HUMAN: Cholesterol (vital to FUNGI: Ergosterol (a sterol
animal cell membrane structure, which has two conjugated
precursor to fat-soluble double bonds, a provitamin
IUPAC NAME: (3β)-cholest-5- form of vitamin D2
en-3-ol IUPAC NAME: ergosta-5,7,22-
trien-3 β -ol
 TISSUE REACTIONS OF FUNGAL DISEASE
A. DERMATOPHYTE INFECTIONS
-erythema (irritation of the tissues by the org.)
-severe inflammation
-scar tissue
-keloid formation

B. SUBCUTANEOUS & SYS. MYCOSES

-uniform acute pyogenic rxn coagulative necrosis and invasion of blood vessels)
-granuloma
-thrombosis (purulent coagulative necrosis and invasion of blood vessels

CLASSES of ANTIFUNGALS (MIXED)

1. FATTY ACIDS (skin pH alteration)
2. PHENOLS & THEIR DERIVATIVES (Cell Amino Acid Transport Blocker)
3. NUCLEOSIDE/PYRIMIDINE ANALOGUE (Nucleic Acid Synthesis Inhibitor)
4. ANTIBIOTICS
a. POLYENES (Cell Membrane Disruption, ‘pore-creating’)
b. NON-POLYENES (Microtubule Polymerization, ‘mitotic spindle formation inhibitor’)
5. ALLYAMINE & REALATED COMPOUNDS (1st Stage Ergosterol Biosynthesis Blocker)
6. AZOLES (Ergosterol Biosynthesis Inhibitor)
a. IMIDAZOLES (Binds at Nitrogen-3)
b. TRIAZOLES (Binds at Nitrogen-4)
7. ECHINOCANDINS/PNEUMOCANDINS (Glucan Synthase Inhibitor)
8. AUREOBASIDIN (Sphingolipid Biosynthesis Inhibitor)
9. NAPHTHACENEQUINONES (Binds with calcium ion to disrupt cell membrane)
10.MORPHOLINES (Ergosterol Biosynthesis Inhibitor)

FATTY ACIDS (B-PRUTZ2S2)

• Sebum –natural antifungal agent on skin
- Acidic, have fatty acid substances in and on the skin
• Advantage of HMW fatty acids –lower volatility
• Salts of Fatty acid –also fungicidal and non-volatile

BENZOIC ACID - antifungal but can’t penetrate ZINC PROPIONATE - – occurs anhydrous form
to outer layer of infected area. and as a monohydrate
- Must be admixed with keratolytic agent SOLUBLE: water, sparingly soluble in alcohol
Ex: Benzoic acid + Salicylic acid (Whitfield’s) USE: adhesive tape

Benzoic acid + Resorcinol

PROPIONIC ACID - non-irritating, non-toxic ZINC CAPRYLATE – fine white powder

- clear, corrosive liquid w/ characteristic INSOLUBLE: water & alcohol
odor
 SOLUBILITY: water & alcohol
SALT FORMS: Na, K, Ca, NH4 (likely used;
non-volatile, odorless)

RESORCINOL - (m-Hydroxyphenol) –antiseptic SODIUM CAPRYLATE –from caprylic acid

and keratolytic USE: Tx for Microsporum, Epidermophyton ssp.
SOLUBLE: water, alcohol, organic solvents. C. albicans, Trichophytons (MECT)

UNDECYCLENIC ACID - better fatty acid used SALICYLIC ACID – antiseptic, keratolytic and poor
for tx tinea pedis fungicide
-(Desenex, Cruex) from destructive distillation of SOLUBLE: Most organic solvents, slightly soluble
castor oil in water
–viscous yellow liquid
SOLUBLE : alcohol and most organic solvents /
water insoluble
TOPICAL: 10% solution, ointments, powders
and emulsions
-Should never be applied in mucous membrane
because it is severe irritant.

TRIACETIN - or Gyceryl triacetate (Enzactin,

Fungacetin) is colorless, oily liquid with a bitter
taste

PHENOL AND THEIR DERIVATIVES

MOA: interfere with cell membrane integrity and
- function in susceptible fungi.
HALOPROGIN (Halotex)– 3-Iodo-2propynyl-2,4,5-trichlorophenyl ether
- Crystallize as white to pale yellow forms
SOLUBLE: sparingly soluble in water and very soluble in ethanol
- Ethereal derivative of phenol.
USE: 1% cream for the tx of superficial tinea infections.

Clioquinol (Vioform): spongy, light sensitive, yellowish white powder; substitute for iodoform

USE: tx of jock itch and athlete’s foot, 3% tx of vaginitis

Ciclopirox olamine (Loprox): a broad spectrum antifungal agent used topically.
Chemical class: Hydroxypyridone
Agent of choice (AOC):cutaneous candidiasis, Tinea corporis, Tinea cruris, Tinea pedis, and Tinea
versicolor. Second line agent for onychomycosis
MOA: Low concentration: block the transport of amino acids into the cell High concentration: lost of
membrane integrity and cellular constituents

NUCLEOSIDE ANTIFUNGAL
Flucytosine (5-FC, Ancobon): orally active, narrow spectrum antifungal agent.
MOA: incorporation of fluorinated pyrimidine to fungal RNA following selective deamination of
5fluouracil, which is an anti-metabolite that inhibits thymidylate synthethase and thus DNA synthesis
Use: tx of systemic Candida and Cryptococcus spp.
infections.
Synergy with amphotericin B has been demonstrated
o The altered permeability of the fungal cell membrane produced by amphotericin allows enhanced
uptake of flucytosine

4 RESISTANCE OF FLUCYTOSINE:
1. Step in w/c drug is transported into the fungal cell. The transport system
2. simply become impermeable to 5-FC
3. In cytosine deaminase step
4. In UMP pyrophosphate reaction

Drug resistance develops rapidly. After dosing intervals, drug will be useless.
SOLUTION TO RESISTANCE:
1. Administer it with polyene antibiotic amphotericin B. It creates a hole in the fungal cell membrane,
bypassing the transport step and allow 5-FC to enter.
2. Lower dose of 5-FC, preventing resistance by other mechanisms for a longer period.
ANTIFUNGAL ANTIBIOTICS (ANNG)
Two CLASSES of antifungal antibiotics:
A. Polyenes – large number with few useful agents
B. Non-polyenes (Griseofulvins) – one member of the class

A. POLYENES - - from Streptomyces, contain conjugated –ene system of double bonds in

macrocyclic lactone rings
Two GROUPS of Polyenes based on macrolide ring:
1. 26-membered-ring polyenes. Ex. Natamycin (pimaricin)
2. 38-membered macrocycles. Ex. Amphotericin B and nystatin

Common to polyenes:
1. a series of OH groups on acid derived portion of the ring
2. glycosidically linked deoxyaminohexose called mycosamine
In vitro low concentration effective against:
 Candida ssp
 C. immitis
 C. neoformans

 H. capsulatum
 B. dermatitidis
 M. mucedo

 Aspergillus fumigatus
 Cephalosporium ssp.
 Fusarium ssp

Use of polyenes in systemic treatment is limited because:

1. toxicities of drug
2. poor chemical stabilities
3. low water solubilites

Amphotericin – only useful polyenes in systemic infections

MOA OF POLYENES:* the three dimensional shape, a barrel like non-polar structure capped by a
polar group (the sugar) , acting as “false membrane components” and bind closely to ergosterol,
causing membrane disruption, cessation of membrane enzyme activity and loss of cellular
constituents, especially potassium ions.
 low concentrations - fungistatic –the polyenes bind to membrane-bound enzyme component,
such as ATPase.
 high concentrations - fungicidal

1. Amphotericin B – from Streptomyces nodusus, where amphotericin A and amphotericin B (more

active) were isolated.
MOA: Binds to ergosterol in fungal membrane causing membrane to become “Leaky”
 An amphoteric substance, with primary amino group attached to the mycosamine ring and
carboxyl group on the macrocycle.
SIDE EFFECTS: Fever, headache, anorexia, gastrointestinal distress, malaise and joint pain.
COMPLICATION: Pain at the site of injection and thrombophlebitis
 Must NEVER be given intramuscularly

Liposomal amphotericin B- specifically tx pulmonary aspergillosis

Topical Amphotericin B: Tx cutaneous and mucocutaneous mycoses by C. albicans.
Oral Amphotericin B: Tx oral and pharyngeal candidiasis (slow resistance)

2. Nystatin – from Streptomyces nourcei

 - 38-membered lactone ring contain single tetraene and diene moieties separated by two
methylene groups. The aglycone contains 8 OH, one carboxyl and lactone ester functionality.
nystanolide- aglycone part of nystatin
SOLUBILITY: slighty soluble (water), sparingly soluble (organic solvents)
ORAL: not absorbed systematically because nearly insoluble
PARENTERAL: toxic
TOPICAL: tx of local and gastromolinial infection by Candida albicans, cutaneous and
mucocutaneous candidiasis
VAGINAL TABLETS: for vaginal candidiasis
ORAL TABLETS AND TROCHES: GI and oral candidasis

COMBINATION W/ NYSTATIN: to prevent molinial overgrowth caused by the destruction of bacterial

microflora of the intestine during tetracycline therapy

3. Natamycin – from Streptomyces natalensis

- 26-membered lactone ring
- Amphoteric
MOA: Cause potassium leakage (fungistatic) and cell lysis (fungicidal) at the same concentration.
In-vitro activity against:
 Candida
 Aspergillus
 Cephalosporium
 Penicillum
 Fusarium

5% opth. susp – tx fungal conjunctivitis, blepharitis and keratitis

B. NON-POLYENE –‘polyene-like’, inhibit fungal cell mitosis

1. Griseofulvin – from Penicillium griseofulvum
- a rare structure, spiro compound
SOLUBILITY: sparingly soluble (water), soluble (alcohol, organic solvents)
USE: Tx of refractory ringworm infection by Trichophyton, Microsporum, and Epidermophyton.
MOA*: inhibits microtubule polymerization thus inhibiting the formation of the mitotic spindle.
o oral bioavailability is poor, because compound is highly lipophilic and low water solubility.
BEST ADVICE OF PHARMACIST: take drug with fatty meal, as with salad dressing.
ADVERSE REACTIONS:
 allergic reactions such as rashes and urticaria
 GI upset
 Headache
 Dizziness
 Insomnia

5. ALLYLAMINES AND RELATED COMPOUNDS (NTT)

MOA: These compounds interfere with an early step in ergosterol biosynthesis, namely the
epoxidation of squalene catalyzed by squalene epoxidase. Inhibition of squalene epoxidase shuts
down the biosynthesis of ergosterol and causes accumulation of squalene, which destabilizes the
fungal cell membrane. Mammalian squalene epoxide weakly inhibited
 Fungicidal – dermatophytes and filamentous fungi
 Fungistatic – pathogenic yeasts, ex Candida
 Naftinine and terbinafine – tx ffor tinea pedis, tines cruris, tinea corporis
 Tolnaftate – inhibits squalene epoxidase but not allylamine

A. ALLYLAMINES
a. Naftifine HCl – white crystalline powder
SOLUBLE: Polar solvents like ethanol and methylene chloride
1% cream and gel – tx for ringworm, athlete’s foot, and jock itch.
Unapproved use: ringworm of the beard, scalp and tinea versicolor.

b. Terbinafine HCl – off-white crystalline material

- 1% cream – tinea pedis, tinea corporis and tinea cruris.
SOLUBLE: polar organic solvents like methanol, ethanol, and methylene chloride.
Slighty soluble (water)
 More potent than naftifine and demonstrated oral against onychomycosis
B. ALLYLAMINE-LIKE
a. Tolnaftate – white crystalline solid
- a thiolester of B-naphthol
- 1% - tx for ringworm, athlete’s foot, and jock itch.
SOLUBLE: most organic solvents. Sparingly soluble (alcohol), insoluble (water)
 Fungicidal: Trichopyhton, Microsporum, and Epidermophyton

6. Azole Antifungal Agents

- Effective against most fungi that causes superficial infections of the skin and mucous
membranes, including the dermatophytes ( Trichophyton, Epidermophyton, & Microsporum
spp.) and yeasts( C. albicans)
MOA:
High in vitro conc. (micromolar) = fungicidal
Low in vitro conc. (nanomolar) = fungistatic
- Fungicidal effect associated with damage to the cell membrane, with the loss of essential
cellular components such as potassium ions and amino acids.
- Function of lanosterol 14ɑ-demethylase: to oxidatively remove a methyl group from lanosterol
during ergosterol biosynthesis
- Higher concentrations of the azoles are needed to inhibit the mammalian enzyme

STRUCTURE-ACTIVITY RELATIONSHIPS

Most potent antifungal azoles possess:

 two or three aromatic rings
 At least one of which is halogen substituted & other nonpolar functional groups
Fluorine- halogen atom that yields the most potent compounds

PRODUCTS
1. Clotrimazole (Lotrimin, Gyne-Lotrimin, Mycelex)
- Broad-spectrum antifungal drug that is used topically for the treatment of tinea infections and
candidiasis
- Extremely stable with a shelf life of more than 5 years
- Not considered suitable for the treatment of systemic infections

2. Econazole Nitrate (Spectazole)

- used as 1% cream for the treatment of local tinea infections and cutaneous candidiasis
3. Butoconazole Nitrate (Femstat)
- extremely broad spectrum antifungal drug that is specifically effective against C.
albicans

4. Sulconazole Nitrate (Exelderm)

 - the salt is used in solution and cream in 1% conc. for the treatment of local tinea infections
such as jock itch, athlete’s foot and ringworm.
5. Oxiconazole Nitrate (Oxistat)
-used in cream and lotion dosage forms in 1% conc. for the treatment of tinea pedis, tinea
corporis, and tinea capitis.

6. Tioconazole (Vagistat)
- used in the treatment of vulvovaginal candidiasis
- More effective against Torulopsis glabrata than are other azoles

7. Miconazole Nitrate (Monistat, Micatin)

- Free base is available in an injectable form, solubilized with polyethylene glycol and castor oil
- Intended for the treatment of serious systemic fungal infections such as candidiasis,
coccidioidomycosis, cryptococcosis, petriellidiosis, and paracoccidioidomycosis.
- It may also be used for the treatment of chronic mucocutaneous candidiasis.

8. Ketocanazole (Nizoral)
- Broad-spectrum imidazole antifungal agent that is administered orally for the treatment of
systemic fungal infections
- Antacids and drugs such as H2 histamine antagonists and anticholinergics that inhibit gastric
secretion interfere with its oral absorption.
- Primary route of excretion is enterohepatic
- High doses lower testosterone and corticosterone levels, reflecting the inhibition of cytochrome
P450-requiring enzymes invoved in human steroid hormone biosynthesis
- Recommended for the treatment of systemic fungal infections
- Used orally to treat severe refractory cutaneous dermatophytic infections not responsive to
topical therapy or griseofulvin.
- Used topically in a 2% conc. In cream and in a shampoo for the treatment of cutaneous
candidiasis and tinea infections.

9. Terconazole (Terazol)
- Triazole derivative
- For the control of the vulvovaginal moniliasis caused by C. albicans and other Candida species

10. Itraconazole (Sporanox)

- A unique member of the azole class that contain two triazole moieties in its structure, a weakly
basic 1,2,4-triazole and nonbasic 1,2,4-triazol-3-one
- Orally active, broad-spectrum antifungal agent
- Important alternative to Ketoconazole
- Used for the treatment of systemic fungal infections
- Food greatly enhances the absorption of itraconazole, nearly doubling its oral bioavailability
- Terminal elimination half-life of itraconazole ranges from 24 to 40 hours
- Can inhibit cytochrome P450 oxidases
 11. Fluconazole (Diflucan)
- water-soluble bis-triazole with broad spectrum antifungal properties that is suitable for both oral
and intravenous administration as the free base
- Oral bioavailability: following administration of either tablet/ oral susp. is excellent.
- relatively long elimination half-life from 27 to 34 hours
- Preferred therapy for coccidioidal meningitis even if it is generally less effective than either
ketoconazole or itraconazole against nonmeningeal coccidioidomycosis
- Lends itself to one dose therapies for vaginal candidiasis
- Agent of choice:
 Treatment of crytococcal meningitis
 Prophylaxis against cryptococcis in AIDS patients

NEWER ANTIFUNGAL STRATEGIES

1. Voriconazole
- Potent activity against a broad variety of fungi, including the clinically important pathogens
- More potent than itraconazole against Aspergillus spp.
2. Posaconazole
- Now in phase III clinical trials
- Undergoes extensive enterohepatic recycling, and most of the dose is eliminated in the bile
and feces

3. Syn2869
-novel broad-spectrum compound that contains the piperazine-phenyl-triazone side chain
common to itraconazole and posaconazole
-demonstrates better activity than itraconazole in animal models of C. albicans, C. glabrata,
and C. neoformans
- demonstrates considerable activity against the common mold pathogens

7. ECHINOCANADINS AND PNEUMOCANADINS

1. Echinocanadin
- Natural products that were discovered in the 1970s
- Act as noncompetitive inhibitors of (1,3)-ß-d-glucan synthase, an enzyme complex that forms
stabilizing glucan polymers in the fungal cell wall

8. AUREOBASIDINS
1. Aureobasidin A
- A cyclic depsipeptide that is produced by fermentation in cultures of Aureobasidium pullulan
- Pradimycins and benanomycins: naphthacenequinones; both demonstrate good in vitro and in
vivo activity against Candida spp. And C. neoformans clinical isolates.