Medicinal Chemistry-III

Anti-fungal antibiotics

Course Leader: Mrs. M. K. Yuvapriya

yuvapriya.py.ph@msruas.ac.in

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 Antifungal antibiotics
• Important group

• Two classes- polyenes and griseofulvin

• Polyenes- complex antifungal antibiotics isolated from soil bacteria of the genus
Streptomyces

• Contain a system of conjugated double bonds in macrocyclic lactone rings

• Different from erythromycin type structures (macrolides)

• Larger and contain the conjugated -ene system of double bonds- called polyenes

• Clinically useful polyenes- two groups- on the basis of size of macrolide ring

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 Antifungal antibiotics
• 26-membered–ring polyenes, such as natamycin (pimaricin) form one group

• 38-membered macrocycles, such as amphotericin B and nystatin, form other group

• Number of double bonds in the macrocyclic ring differs also

• Natamycin, the smallest macrocycle, is a pentaene;

• Nystatin is a hexaene; and

• Amphotericin B is a heptaene

• polyenes have no activity against bacteria, rickettsia, or viruses

• Highly potent, broad-spectrum antifungal agents

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 Antifungal antibiotics
• Use of the polyenes for the treatment of systemic infections is limited

• toxicities of the drugs,

• Low water solubilities, and

• poor chemical stabilities

• Amphotericin B, the only polyene useful for the treatment of serious systemic
infections, must be solubilized with a detergent

• Other polyenes are indicated only as topical agents for superficial fungal infections

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 Mechanism of action
• In three-dimensional shape,

• a barrel-like nonpolar structure capped by a polar group (sugar)

• penetrate the fungal cell membrane, acting as “false membrane components,”

• bind closely with ergosterol,

• causing membrane disruption,

• cessation of membrane enzyme activity, and

• loss of cellular constituents, especially potassium ions

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 Amphotericin B
• Purified from the soil culture of the actinomycete Streptomyces nodosus, which was
isolated in Venezuela

• first isolate from the streptomycete was a separable mixture of two compounds,
designated amphotericins A and B

• In test cultures, compound B proved to be more active, and this is the one used
clinically

• Amphotericin B is believed to interact with membrane sterols (ergosterol in fungi) to

produce an aggregate that forms a transmembrane channel

• Intermolecular hydrogen bonding interactions among hydroxyl, carboxyl, and amino

groups stabilize the channel in its open form
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 Amphotericin B
• allowing the cytoplasmic contents to leak out

• This explains the toxicity in human patients

• Is an amphoteric substance, with a primary amino group attached to the

mycosamine ring and a carboxyl group on the macrocycle

• Forms deep yellow crystals that are sparingly soluble in organic solvents but
insoluble in water

• To create a parenteral dosage form, amphotericin B is stabilized as a buffered

colloidal dispersion in micelles with sodium deoxycholate

• Nearly 80% of patients treated with amphotericin B develop nephrotoxicity

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 Amphotericin B
• Fever, headache, anorexia, gastrointestinal distress, malaise, and muscle and joint
pain are common

• Pain at the site of injection and thrombophlebitis are frequent complications of

intravenous administration.

• Drug must never be administered intramuscularly.

• Hemolytic activity of amphotericin B may be a consequence of its ability to leach

cholesterol from erythrocyte cell membranes

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 Amphotericin B
• Drug is supplied in various topical forms, including a 3% cream, a 3% lotion, a 3%
ointment, and a 100-mg/mL oral suspension

• Nystatin

• First isolated in 1951 from a strain of the actinomycete Streptomyces noursei by

Hazen and Brown

• very slightly soluble in water and sparingly soluble in organic solvents

• unstable to moisture, heat, and light

• aglycone portion of nystatin is called nystatinolide

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 Nystatin
• It consists of a 38-membered macrolide lactone ring containing single tetraene and
diene moieties separated by two methylene groups

• Aglycone also contains eight hydroxyl groups, one carboxyl group, and the lactone
ester functionality

• Entire compound is constructed by linking the aglycone to mycosamine

• not absorbed systemically when administered by the oral route

• It is nearly insoluble under all conditions

• It is also too toxic to be administered parenterally and used only as a topical agent

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 Nystatin
• Valuable agent for the treatment of local and gastrointestinal monilial infections
caused by C. albicans and other Candida species

• For the treatment of cutaneous and mucocutaneous candidiasis, it is supplied as a

cream, an ointment, and a powder

• Oral tablets are used in the treatment of gastrointestinal and oral candidiasis

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 Natamycin

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 Natamycin
• Polyene antibiotic obtained from cultures of Streptomyces natalensis

• consists of a 26-membered lactone ring containing a tetraene chromophore,

• an α,β-unsaturated lactone carbonyl group, three hydroxyl groups, a carboxyl group,

a trans epoxide, and a glycosidically joined mycosamine

• natamycin is amphoteric

• Mechanism- 26-membered–ring polyenes cause both potassium ion leakage and cell
lysis at the same concentration

• whereas the 38-membered–ring polyenes cause potassium leakage at low,

fungistatic concentrations and cell lysis at high, fungicidal concentrations
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 Natamycin
• smaller polyenes are fungistatic and fungicidal within the same concentration range

• supplied as a 5% ophthalmic suspension intended for the treatment of fungal

conjunctivitis, blepharitis, and keratitis

• Griseofulvin

• antibiotic obtained from the fungus Penicillium griseofulvum

• It was isolated originally as a “curling factor” in plants

• drug has been used for many years for its antifungal action in plants and animals

• In 1959, griseofulvin was introduced into human medicine for the treatment of tinea
infections by the systemic route
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 Griseofulvin

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 Griseofulvin
• example of a rare structure in nature, a spiro compound

• compound is a white, bitter, heat-stable powder or crystalline solid

• sparingly soluble in water but soluble in alcohol and other nonpolar solvents

• used for a long time for the systemically delivered treatment of refractory ringworm
infections of the body, hair, nails, and feet

• caused by species of dermatophytic fungi including Trichophyton, Microsporum and

Epidermophyton

• Griseofulvin neither possesses antibacterial activity nor is effective against P.

obiculare, the organism that causes tinea versicolor
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 Griseofulvin
• most common ones are allergic reactions such as rash and urticaria, gastrointestinal
upset, headache, dizziness, and insomnia

• oral bioavailability of griseofulvin is very poor

• compound is highly lipophilic with low water solubility

• Several structural derivatives have been synthesized, but they have failed to improve
absorption

• best advice that the pharmacist can give a patient who is about to use griseofulvin is
to take the drug with a fatty meal

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 Synthetic anti-fungal agents
• Clotrimazole, Econazole, Butoconazole, Oxiconazole Tioconozole Ketoconazole,
Terconazole, Itraconazole, Fluconazole, Naftifine hydrochloride

• Synthesis- Miconazole, Tolnaftate

• Azole Antifungal Agents

• Possess a unique mechanism of action

• Can achieve selectivity for the infecting fungus over the host

• Can treat infections ranging from simple dermatophytoses to life-threatening, deep

systemic fungal infections

• First members of the class were highly substituted imidazoles, such as clotrimazole
and miconazole 21
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 Azole Antifungal Agents
• 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

• Spectrum of activity

• Azoles tend to be effective against most fungi that cause superficial infections of the
skin and mucous membranes, including the dermatophytes such as Trichophyton,
Epidermophyton, and Microsporum spp. and yeasts such as C. albicans

• On the other hand, they also exhibit activity against yeasts that cause systemic
infections, including C. immitis, C. neoformans, Paracoccidioides brasiliensis,
Petriellidium boydii, B. dermatitidis, and H. capsulatum 22
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 Azole Antifungal Agents- Mechanism of action
• At micromolar, the azoles are fungicidal

• At nanomolar, the azoles 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

• Fungistatic effect is associated with inhibition of membrane-bound enzymes

• A cytochrome P450-class enzyme, lanosterol 14α-demethylase, is the likely target for

the azoles

• Function of lanosterol 14α-demethylase is to oxidatively remove a methyl group from

lanosterol during ergosterol biosynthesis
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 Azole Antifungal Agents- Mechanism of action

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 Azole Antifungal Agents- Mechanism of action
• Lanosterol 14α-demethylase is also required for mammalian biosynthesis of
cholesterol, and the azoles are known to inhibit cholesterol biosynthesis

• Higher concentrations of the azoles are needed to inhibit the mammalian enzyme

• Provides selectivity for antifungal action

• 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

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 Clotrimazole
• Broad-spectrum antifungal drug that is used topically for the treatment of tinea
infections and candidiasis

• It occurs as a white crystalline solid that is sparingly soluble in water but soluble in
alcohol and most organic solvents

• It is a weak base that can be solubilized by dilute mineral acids

• Extremely stable, with a shelf life of more than 5 years

• Effective against various pathogenic yeasts and

• Reasonably well absorbed orally, extensively protein bound

• Not considered suitable for the treatment of systemic infections

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 Econazole
• It is only slightly soluble in water and most organic solvents

• Used as a 1% cream for the topical treatment of local tinea infections and cutaneous
candidiasis

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 Butoconazole
• Extremely broad-spectrum antifungal drug that is specifically effective against C.
albicans

• It is intended for the treatment of vaginal candidiasis- 2% of butoconazole nitrate in

the form of cream

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 Oxiconazole
• It is used in cream and lotion dosage forms in 1% concentration for the treatment of
tinea pedis, tinea corporis, and tinea capitis

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 Tioconazole
• Used for the treatment of vulvovaginal candidiasis

• A vaginal ointment containing 6.5% of the free base is available

• More effective against Torulopsis glabrata than are other azoles

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 Miconazole
• Occurs as white crystals that are sparingly soluble in water and most organic solvents

• The free base is available in an injectable form, solubilized with polyethylene glycol
and castor oil, and intended for the treatment of serious systemic fungal infections

• Like candidiasis, coccidioidomycosis, cryptococcosis, petriellidiosis, and

paracoccidioidomycosis

• thrombophlebitis, pruritus, fever, and gastrointestinal upset are relatively common

side effects

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 Ketoconazole
• broad-spectrum imidazole antifungal agent that is administered orally for the
treatment of systemic fungal infections

• It is a weakly basic compound that occurs as a white crystalline solid that is very
slightly soluble in water

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 Ketoconazole
• primary route of excretion is enterohepatic

• It is estimated to be 95% to 99% bound to protein in the plasma

• Hepatotoxicity- most serious adverse effect

• known to inhibit cholesterol biosynthesis in both mammals and fungi

• High doses have also been reported to lower testosterone and corticosterone levels

• Ketoconazole is a racemic compound, consisting of the cis-2S,4R and cis-2R,4S

isomers

• trans-isomers, 2S,4S and 2R,4R, are much less active

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 Ketoconazole
• recommended for the treatment of the following systemic fungal infections:
candidiasis (including oral thrush and the chronic mucocutaneous form),
coccidioidomycosis, blastomycosis, histoplasmosis, chromomycosis, and
paracoccidioidomycosis

• It is also used orally to treat severe refractory cutaneous dermatophytic infections

not responsive to topical therapy or oral griseofulvin

• antifungal actions of ketoconazole and the polyene antibiotic amphotericin B are

reported to antagonize each other

• used topically in a 2% concentration in a cream and in a shampoo for the

management of cutaneous candidiasis and tinea infections 34
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 Terconazole
• Triazole derivative that is used exclusively for the control of vulvovaginal moniliasis
caused by C. albicans and other Candida species

• It is available in creams containing 0.4% and 0.8% of the free base intended for 7-day
and 3-day treatment periods, respectively

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 Itraconazole
• Unique member of the azole class that contains two triazole moieties in its structure

• A weakly basic 1,2,4-triazole and a non-basic 1,2,4-triazol-3-one

• orally active, broad-spectrum antifungal agent and important alternative to

ketoconazole

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 Itraconazole
• An acidic environment is required for optimum solubilization and oral absorption

• Food greatly enhances the absorption of itraconazole, nearly doubling its oral
bioavailability

• drug is avidly bound to plasma proteins (nearly 99% at clinically effective

concentrations) and extensively metabolized in the liver

• Only one of the numerous metabolites, namely 1-hydroxyitraconazole, has significant

antifungal activity

• terminal elimination half-life of itraconazole ranges from 24 to 40 hours

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 Itraconazole
• Used for the treatment of systemic fungal infections including blastomycosis,
histoplasmosis (including patients infected with [HIV]),

• nonmeningeal coccidioidomycosis, paracoccidioidomycosis, and sporotrichosis

• It may also be effective in the treatment of pergellosis, disseminated and deep organ
candidiasis, coccidioidal meningitis, and cryptococcosis

• Unlike ketoconazole, it is not hepatotoxic and does not cause adrenal or testicular
suppression in recommended therapeutic doses

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