DR.Narmin Hamaamin Hussen

1. Antifungal Drugs
Lecture 2
Medicinal Chemistry IV / 2nd Semester / 4thClass
Dr.Narmin Hamaamin Hussen
2022-2023
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2. AntifungalDrugs
▪ Antifungal medicines are used to treat fungal infections, which most commonly affect
your skin, hair and nails.
▪ Fungal infections commonly treated with antifungals include:
a. ringworm
b. athlete's foot
c. fungal nail infection
d. vaginal thrush
e. some types of severe dandruff
▪ Some fungal infections can grow inside the body and need to be treated in hospital.
Examples include:
a. aspergillosis, which affects the lungs
b. fungal meningitis, which affects the brain
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3. Types of fungal infections
1. Superficial : Affect skin – mucous membrane.
a) Tinea versicolor, Dermatophytes : Fungi that affect keratin layer of skin, hair, nail.e.g.tinea pedis ,ring worm
infection
b) Candidiasis : Yeast-like, oral thrush, vulvovaginitis , nail infections.
2. Affect internal organs as : lung ,heart , brain leading to pneumonia , endocarditis , meningitis
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4. Biochemical Targets for Antifungal Chemotherapy
▪ Antifungal chemotherapy depends on
biochemical differences between fungi
and mammals
▪ Unlike bacteria, which are prokaryotes,
both fungi and mammals are eukaryotes
▪ The fungal cell wall
▪ Other targets for antifungal agents
include inhibitors of DNA biosynthesis,
▪ Sterols
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5. Fungal Cell Wall
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6. Classification of antifungal drugs based on structure
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7. Classification of antifungal drugs based on mechanism of action
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8. Antifungal antibiotics
1- Polyene antibiotics :Nystatin& Amphotericin B
2- Heterocyclic Benzofuran: Griseofulvin
Polyene antibiotics (polyene = many double bonds )
➢ Nystatin
▪ Nystatin the first clinically useful polyene antifungal antibiotic, is a conjugated tetraene isolated from cultures
of the bacterium Streptomyces noursei in 1951 .
▪ It is used to treat Candida infections of the skin including diaper rash, thrush, esophageal
candidiasis,gastrointestinal candidiasis and vaginal yeast infections.
▪ Nystatin is too toxic to be used systemically, but because very little drug is absorbed following oral
administration, it may be administered by mouth to treat fungal infections of the mouth and gastrointestinal
tract
▪ It is a similar in structure & mechanism to amphotericin B
▪ Nystatin acts by binding to sterols in the cell membrane of susceptible fungi with a resultant change in
membrane permeability allowing leakage of intracellular components.
▪ Nystatin is an effective topical antifungal against a wide variety of organisms and is available in a variety of
creams and ointments.
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9. ➢ Amphotericin B
▪ It is an amphoteric compound that consists of seven-conjugated double bond, an internal ester, a free carbonyl group, and a
glycoside side chain with a primary amino group.
▪ The carbohydrate moiety is D-mycosamine. The conjugated systems are usually of all trans configurations, so that the ring
contains a planner lipophilic segment and a less rigid hydrophilic portion.
▪ Amphotericin B, which as a heptaene has low enough toxicity to mammalian cells to permit intravenous (IV)
administration, was discovered in 1956.
▪ The 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 injection is used to treat serious and potentially life-threatening fungal infections( Systemic Fungal
Infections, Cryptococcal Meningitis, Visceral Leishmaniasis and black fungus)
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10. 10
▪ Amphotericin B is a very toxic drug and must be used with caution.
▪ Adverse effects include fever, shaking chills, hypotension, and severe kidney toxicity.
▪ More recently developed formulations of amphotericin B, such as liposomal encapsulation and lipid complexes, have
dramatically decreased the toxicity of the drug to humans, which permits higher plasma levels to be employed .
▪ The mechanisms by which the new formulations decrease the toxicity are not entirely clear, but altered distribution is
clearly a factor. Because the blood vessels at the site of infection are more permeable than those of normal tissue, the
large suspended particles of the lipid formulations can penetrate the site of infection more readily than they can
penetrate healthy tissue. The result is selective delivery of drug to the site of infection.
▪ Some evidence also indicates that the newer formulations transfer amphotericin B to ergosterol- containing fungal cells
more efficiently than to cholesterol-containing mammalian cell
▪ The drug cannot cross the blood–brain barrier and must be administered intrathecally for treatment of fungal
infections of the CNS.

11. Mechanism of Action
▪ The lipophilic polyene portion crosses the cell lipid bilayer forming a pore in the cell membrane
▪ Polyenes have a demonstrably higher affinity for membranes containing ergosterol over cholesterol-
containing membranes . This is the basis for their greater toxicity to fungal cells.
▪ 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, destroying symport activity and allowing
the cytoplasmic contents to leak out. The effect is similar with cholesterol
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12. What is 'Black Fungus' or 'Mucormycosis (Zygomycosis)'?: Symptoms and treatment
▪ Mucormycosis, commonly called black fungus, is a serious and rare fungal infection
affecting those suffering from coronavirus in India.
▪ The black fungus that invades the brain is being increasingly seen in vulnerable
patients in India as the health system continues to struggle amid the pandemic.
▪ This infection caused by a group of fungi called mucormycetes. These are ubiquitous
in the environment and can often be seen on rotting food. Despite being common in
the environment, it doesn’t cause infection in humans as our immune cells can easily
fight such pathogens.
▪ Mucormycosis is a deadly fungal infection found in some Covid-19 patients with
uncontrolled diabetes and prolonged intensive care unit (ICU) stay
▪ In COVID-19 patients with diabetes and immuno-suppressed individuals, one must
suspect mucormycosis if there is sinusitis, one-side facial pain or numbness, blackish
discolouration over the bridge of the nose or palate, toothache, blurred or double
vision with pain, skin lesion, thrombosis, chest pain and worsening respiratory
symptoms, it said
▪ Medical treatment (Amphotericin B infusion and anti-fungal therapy for at least six
weeks)
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13. Heterocyclic Benzofuran:
➢ Griseofulvin
▪ Griseofulvin is an antifungal antibiotic produced by an unusual strain of Penicillium .
▪ Griseofulvin is an antifungal medication used to treat a number of types of dermatophytoses
(ringworm). It is used orally to treat superficial fungal infections, primarily fingernail ,toenail and
scalp infections, but it does not penetrate skin or nails if used topically .
▪ The mechanism of action of griseofulvin is through binding to the protein tubulin, which interferes
with the function of the mitotic spindle and, thereby, inhibits cell division. Griseofulvin also may
interfere directly with DNA replication.
▪ Griseofulvin is absorbed best when it is taken with a high fat meal, such as a cheeseburger, whole
milk, or ice cream.
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14. Antifungal Azoles
▪ Antifungal Azoles are synthetic drugs with broad-spectrum fungistatic activity. Azoles can be divided into two
groups:
➢ Azole- imidazole agents (clotrimazole, ketoconazole, miconazole) in which the five-member azole nucleus
contains two nitrogens
➢ Newer azole-triazole compounds (fluconazole, itraconazole, and voriconazole), in which the azole nucleus
contains three nitrogens.
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15. Mechanism of action
▪ All the azoles act by inhibiting ergosterol biosynthesis through
inhibition14a-demethylase, CYP50.
▪ Azoles exert antifungal activity by inhibiting cytochrome P450
enzymes responsible for the demethylation of lanosterol to
ergosterol. Reduced fungal membrane ergosterol
concentrations result in damaged, leaky cell membranes.
▪ The toxicity of these drugs depends on their relative affinities
for mammalian and fungal cytochrome P450 enzymes. The
triazoles tend to have fewer side effects, better absorption,
better drug distribution in body tissues, and fewer drug
interactions.
▪ The basic N3 atom of the azole forms a bond with the heme
iron of the CYP450 prosthetic group in the position normally
occupied by the activated oxygen . The remainder of the azole
antifungal forms bonding interactions with the apoprotein in a
manner that determines the relative selectivity of the drug for
the fungal demethylase versus other CYP450 enzymes
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16. 1. The basic structural requirement for members of the azole class is a
weakly basic imidazole or 1,2,4-triazole ring (pKaof 6.5–6.8) bonded
by a nitrogen–carbon linkage to the rest of the structure.
2. 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.
3. 3. 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.
4. Only 2, and/or 2,4 substitution yields effective azole compounds.
5. The halogen atom that yields the most potent compounds is
fluorine, although functional groups such as sulfonic acids have been
shown to do the same.
6. Substitution at other positions of the ring yields inactive
compounds.
7. Presumably, the large nonpolar portion of these molecules mimics
the nonpolar steroidal part of the substrate for lanosterol 14-
demethylase, lanosterol, in shape and size.
8. The nonpolar functionality confers high lipophilicity to the
antifungal azoles.
9. The free bases are typically insoluble in water but are soluble in
most organic solvents, such as ethanol.
10. .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 16

17. Imidazole antifungal agents
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18. ➢ Ketoconazole
▪ Ketoconazole , an imidazole antifungal, was the first orally active antifungal azole to be discovered and, as a
consequence, has been widely studied and employed for the treatment of systemic fungal infections, primarily
candidiasis. Ketoconazole has little effect on Aspergillus or Cryptococcus.
▪ Ketoconazoleis a highly lipophilic compound. This property leads to high concentrations of ketoconazole in fatty
tissues and purulent exudates.
▪ Ketoconazole is highly dependent on low stomach pH for absorption, and antacids or drugs that raise stomach
pH will lower the bioavailability of ketoconazole.
▪ Evidence that CYP3A4 plays a significant role in metabolism of ketoconazole is that coadministration of CYP3A4
inducers, such as phenytoin, carbamazepine, and rifampin, can cause as much as a 50% reduction in levels of
ketoconazole
▪ Ketoconazole also is a powerful inhibitor of human CYP3A4 and, as a consequence, has many serious
interactions with other drugs. For example, coadministration of ketoconazole with the hypnotic triazolam
results in a 22-fold increase in triazolam’s area under the curve (AUC) and a sevenfold increase in half-life.
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19. Azole-Triazole compounds
➢ Fluconazole
▪ Fluconazole does not require an acidic environment, as does ketoconazole, for GI absorption. About 80 to 90% of an orally
administered dose is absorbed, yielding high serum drug levels. The t1/2 of the drug is 27 to 37 h, permitting once-daily
dosing in patients with normal renal function.
▪ The drug penetrates widely into most body tissues. Cerebrospinal fluid levels are 60 to 80% of serum levels, permitting
effective treatment for fungal meningitis.
▪ Fluconazole , which was introduced at the same time as itraconazole, differs from ketoconazole and itraconazole in that it is
equally bioavailable when given orally or IV.
▪ Two major advantages of fluconazole over other antifungal agents are that it can cross the blood–brain barrier and has
efficacy against Cryptococcus neoformans . Fluconazole also differs in that it is only a weak inhibitor of CYP3A4 but a
strong inhibitor of CYP2C9 .
▪ Fluconazole is very effective in the treatment of infections with most Candida spp. Thrush in the end-stage AIDS patient,
often refractory to nystatin, clotrimazole, and ketoconazole, can usually be suppressed with oral fluconazole. AIDS patients
with esophageal candidiasis also usually respond to fluconazole. A single 150 mg dose has been shown to be an effective
treatment for vaginal candidiasis. A 3-day course of oral fluconazole is an effective treatment for Candida urinary tract
infection. Stable non-neutropenic patients with candidemia can be adequately treated with fluconazole
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20. ➢ Voriconazole
▪ Voriconazole is a fluconazole analog that was developed to overcome some of
the limitations of fluconazole and does, indeed, have a broader spectrum of
activity than fluconazole, having activity against Aspergillus and fluconazole-
resistant strains of Candida and Cryptococcus .
▪ Voriconazole is orally absorbed and penetrates the blood–brain barrier.
Unfortunately, voriconazole is extensively metabolized CYP450 enzymes and is
an inhibitor of CYP2C19, CYP2C9, and CYP3A4, leading to many drug
interactions
➢ Posaconazole
▪ Posaconazole , a recently introduced triazole, has a number of advantages
over previous agents . Posaconazole has a wide spectrum of activity
compared to other azoles, particularly against Aspergillus and other
increasingly common nosocomial infections resistant to treatment by
other antifungal drugs.
▪ Posaconazole is structurally similar to itraconazole and saperconazole,
but it contains a tetrahydrofuran ring in place of the dioxolan ring of
those agents, which may account for some of its unique properties.
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21. Allyl amines and Other Squalene Epoxidase Inhibitors
➢ Terbinafine, Tolnaftate and Naftifine
▪ The group of agents generally known as allylamines strictly includes only naftifine and terbinafine, but
because butenafine and tolnaftate function by the same mechanism of action, they are included in this
class.
▪ Allyl amines reversible noncompetitive
of the fungal enzyme squalene
inhibitors
epoxidase,
lanosterol.
which
With a
converts squalene to
decrease in lanosterol
ergosterol production is also
production,
diminished, affecting fungal cell membrane
synthesis and function. These agents exhibit
fungicidal activity against dermatophytes and
fungistatic activity against yeasts. Squalene
epoxidase forms an epoxide at the C2–C3
studies in the series
position of squalene
▪ Structure–activity
subsequently led to the discovery of
compounds with enhanced potency and
potential oral activity, such as terbinafine.
X
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22. ➢ Terbinafine
▪ Terbinafine is available in both topical and oral dosage forms and is effective against a
variety of dermatophytic infections when employed topically or systemically . A unique
▪ property of terbinafine is its effectiveness in the treatment of onychomycoses (nail
infections) .
▪ Given orally, the highly lipophilic drug redistributes from the plasma into the nail bed and
into the nail itself, where the infection resides , making terbinafine superior to other
agents for treating this particular type of infection.
➢ Naftifine
▪ Naftifine was the first allylamine to be discovered and marketed . Because of its extensive first-pass
metabolism, naftifine is not used orally and is only available in topical preparations.
▪ The widest use of naftifine is against various tinea infections of the skin.
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23. Inhibitors of Cell Wall Biosynthesis (inhibition of the enzyme β-1,3-glucan synthase)
➢ Echinocandins
▪ Echinocandins, a group of cyclic peptides with long lipophilic side chains and
sometimes called lipopeptides, have been under investigation for a number
of years .
▪ Echinocandins interfere with cell wall biosynthesis through inhibition of the
enzyme β-1,3-glucan synthase.
▪ β-Glucan is an important polymer component of many fungal cell walls, and
reduction in the glucan content severely weakens the cell wall, leading to
rupture of the fungal cell.
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24. ➢ Caspofungin
▪ Caspofungin is a semisynthetic lipopeptide. It inhibits the synthesis of beta-D-glucan, a cell wall component of
filamentous fungi.
▪ Caspofungin is approved for the treatment of invasive aspergillosis in patients not responding to amphotericin
B, and itraconazole.
▪ Adverse effects are mediated through histamine release: facial flushing, rash, fever, and pruritus. Dose
reductions are required in the presence of moderate hepatic insufficiency.
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25. Fluorinated pyrimidines
➢ Flucytosine
▪ Flucytosine (5-flucytosine, 5-FC) is an analogue of cytosine that was originally synthesized for possible use as
an antineoplastic agent
▪ Flucytosine is a powerful antifungal agent used in the treatment of serious systemic fungal infections, such as
Cryptococcus neoformans and Candida spp
▪ Flucytosine itself is not cytotoxic but, rather, is a prodrug that is taken up by fungi and metabolized to 5-fl
uorouracil (5-FU) by fungal cytidine deaminase . Then, 5-FU is converted to 5-fluorodeoxyuridine, which is a
thymidylate synthase inhibitor that interferes with both protein and RNA biosynthesis. 5-Fluorouracil is
cytotoxic and is employed in cancer chemotherapy
▪ Human cells do not contain cytosine deaminase and, therefore, do not convert flucytosine to 5-FU. Some
intestinal flora, however, do convert the drug to 5-FU, so human toxicity does result from this metabolism.
▪ Resistance rapidly develops to flucytosine when used alone, so it is almost always used in conjunction with
amphotericin B. Use of flucytosine has declined since the discovery of fluconazole
Flucytosine, a prodrug, is converted by fungal cytosine deaminase to 5-fluorouracil (5-FU). This reaction does not occur in mammalian cells. A further
transformation of 5-FU to the actual cytotoxic agent 5-fluorodeoxyuridinemonophosphate (5-FdUMP) also occur
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26. ✓ What is liposomal encapsulation? How does
liposome drug delivery work?
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27. Thank You
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