ANTIFUNGAL GROUP 1.pptx

GROUP MEMBERS
AHIMBISIBWE RITAH 2018-08-02239
NAMISI VANESSA 2018-08-00765
NANSUBUGA RUTH 2018-08-02611
KISAKYE JEMIMAH 2018-08001549
OMARA CHARLES 2018-08-04241
MUKWAYA ETHAN ASANASIO 2018-08-00280

Fungalinfections Superficial/Systemic
Tineacorporis
Tinea capitis
Tinea unguium (onychomycosis)
Tinea pedis (Athlethe’s foot)
Tinea cruris (jockitch)
Superficial
(skin, hair, andnails)
Candidaalbicans
Cryptococcusneoformans
Superficial (oral, vaginal,skin
and nails )/Systemic
Systemic
Blastomycesdermatidus Systemic
Aspergillosis Systemic

CLASSIFICATION OF ANTIFUNGALS.
1) ACCORDING TO CHEMICAL STRUCTURE.
POLYENES FATTY ACIDS:
zinc propionate, sodium capryLate
Amphotericin B, Nystatin
AZOLES ECHINOCANDINS:
caspofungin,micafungin
Imidazole: ketoconazole, clotrimazole
Triazoles: fluconazole, itraconazole, PHENOLS AND THEIR DERIVATIVES
voriconazole, Posaconazole Ciclopirox, clioquinol, haloprigin
ALLYLAMINES: Terbinafine, Naftifine, PYRIMIDINE ANALOGUE: Flucytosine
tolnaftate, Butenafine
MORPHOLINE: Amorolfine. NON POLYENE ANTIBIOTIC: Griseofulvin

1-Inhibitors of Cell
Membrane and itsFunction
A-Drugs affecting cell membranefunction
Polyenes (Nystatin - AmphotericinB)
B-Inhibitors of ergosterolsynthesis
1-Azoles
❑Imidazoles (Clotrimazole, Miconazole,Ketoconazole)
❑Triazoles (Itraconazole, Posaconazole, Fluconazole, Voriconazole)
2-Allylamines Terbanafine ,Tolnaftate
3-Morpholines (Amorolfine)
2- Inhibitors of DNA/RNAFunctions
Flucytosin -Griseofulvin
3- Inhibitors of Cell WallFunctions
Echinocandins (Caspofungin)
Classification
of
Antifungal
Drugs

POLYENES
•The polyenes are macrocyclic lactones with
distinct hydrophilic and lipophilic regions.
•The hydrophilic region contains several
alcohols , carboxylic acid and usually a
sugar.
•The lipophilic region contains a
chromophore of 4-7 conjugated double
bonds

Primary amine
Mycosamine
Amnio sugar
C
arboxylic
acid
amphoteric: hasacidic
and basicgroup
Largelactone ring (38membered)

POLYENES
The clinically useful polyenes fall into two
groupings on the basis of the size of the
macrolide ring.
The26-membered–ring polyenes, such
as natamycin (pimaricin),
form one group,
whereas the 38-membered
macrocycles,
such as amphotericin B and nystatin,
form the other group.

MOA
Because of their three-dimensional
shape, a barrel-like nonpolar structure
capped by a polar group (the sugar),
they penetrate the fungal cell membrane,
acting as "false membrane components,”
and bind closely with ergosterol, causing
membrane disruption, cessation of
membrane enzyme activity, and loss of
cellular constituents, especially
potassium ions.

creates an ion-channel
Tunneling( loss of essential cell constituents
(e.g. K+)( cell death
Mechanism of action
binds to hydrophobic
region of ergosterol
forming a hydrophilic
channel
Polyenes

MOA
In fact, the first observable in vitro reaction upon
treating a fungal culture with amphotericin B is
the loss of potassium ions.
The drug is fungistatic at low concentrations
Fungicidal at high concentrations.

STRUCTURAL DIFFERENCE BETWEEN CHOLESTEROL AND
ERGOSTEROL

➢Thenumber of conjugated double bonds (nystatin =4; amphotericin =7)
➢Amphotericin B: the highest activity and the lowest toxicity
SARS OF POLYENES

SARS CONTINUED
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. This explains
the toxicity in human patients

AMPHOTERICIN B
Amphoteric in nature.
It is indicated for the treatment of severe, potentially
life-threatening fungal infections, including
disseminated forms of coccidioidomycosis and
histoplasmosis, sporotrichosis, North American
blastomycosis, cryptococcosis, mucormycosis, and
aspergillosis.
It has a poor oral availability
Has a half life of 15 hours.
Its not metabolized, excreted unchanged .

Amphotericin B
Side effects
Nephrotoxicity
fever
Anorexia
Gastro intestinal distress
Headache
Malaise
Muscle and joint pain.
Formulation to curb side effects
Lipid encapsulation and lipid
complexes dramatically reduced
the toxicity of the drug to humans
by reducing the distribution of the
drug hence increasing plasma
levels.
This is due to the fact that blood
vessels at the site of infection are
more permeable to the large lipid
particles compared to healthy
tissue.

Nystatin
It is a conjugated tetraene.
It was the first polyene to be discovered.
It is used topically . Too toxic to be used systemically.
It is used in ointments and creams.
Due to its poor oral availability , it is used to treat fungal
infections of the mouth and gastro-intestinal tract.
Vaginal tablets are available for the control of vaginal
candidiasis.
Oral tablets and troches are used in the treatment of
gastrointestinal and oral candidiasis

NATAMYCIN
The natamycin structure consists of a 26-membered lactone
ring containing a tetraene chromophore, an ,-unsaturated
lactone carbonyl group, three hydroxyl groups, a carboxyl group,
a trans epoxide, and a glycosidically joined mycosamine.
The mechanism action of the smaller polyenes differs from
that of amphotericin B and nystatin. The 26-membered–ring
polyenes cause both potassium ion leakage and cell lysis at
the same concentration

9
B- Inhibitors of ergosterol synthesis
1- Azoles
❑ Imidazoles (Clotrimazole, Miconazole, Ketoconazole)
❑Triazoles (Itraconazole, Posaconazole, Fluconazole, Voriconazole)
2 Allylamines Terbanafine &Tolnaftate
3 Morpholines (Amorolfine)

α
∆
10
Ergosterol
Biosynthesis
Inhibitors
14α-CH3
(3)
Morpholines
(1) allylamines
(2) azoles
❑Squalene
epoxidase
Inhibitors → 1.
Allylamines
❑Lanosterol 14α-
demethylase
Inhibitors → 2.
Azoles
❑∆14-Reductase
Inhibitors
→ 3. Morpholines
Three enzymes can be
inhibited in this pathway

Azoles
N
N
H
imidazole
N
N
N
H
triazole
❑ Clotrimazole
❑ Miconazole
❑ Ketoconazole
❑ Itraconazole
❑ Posaconazole
❑ Fluconazole
❑ Voriconazole

MOA OF AZOLES
Inhibit cytochrome P450-class enzyme called
lanosterol 14-demethylase by binding to the CYP450
heme moiety preventing the demethylation of
lanosterol to ergosterol .
This causes accumulation of lanosterol and
formation of a weak cell membrane without
ergosterol
.

SARS OF AZOLES.
• The basic structural requirement for members of the azole class is a
weakly basic imidazole or 1,2,4-triazole ring bonded by a nitrogen–
carbon linkage to the rest of the structure.
• 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, atleast one of which is halogen substituted.
• Only 2, and/or 2,4 substitution yields effective azole compounds.
Substitution at other positions of the ring yields inactive compounds

SARS CONTINUED
• 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.
• 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

IUPAC NAME : 1-Acetyl-4-[4-[[2-(2,4-
dichlorophenyl)-2(1H-imidazole-1-ylmethyl)-1,3-
dioxolan-4-yl]methoxy]phenyl]piperazine.
It is a broad-spectrum imidazole antifungal agent
that is administered orally for the treatment of
systemic fungal infections.
Ketoconazole is extensively metabolized to
inactive metabolites, and the primary route of
excretion is enterohepatic.
It is estimated to be 95% to 99% bound to protein
in the plasma.
IMIDAZOLES
KETOCONAZOLE

❑Thefirst orally active
antifungal azole.
❑Oral bioavailability only at low stomach pH < 4, antacids and
H2-histamine antagonists which decrease stomach acidity reduce
absorption. As acid medium is required for protonation and
solublization of thedrug.

➢Imidazole: N3
➢Triazole: N4
1
1
2
2
3
3
4
Protonation of the most basic nitrogen provides a stabilized conjugate acid
by resonance.
❑ N1 lone pair is involved
in resonance, therefore
not basic.
❑ N1 lone pair is involved
in resonance.
❑ N2 lone pair is less
available due to the
electron-withdrawing
effect of the adjacent
electronegative N1.
Reason why a low pH is needed for absorption.

SIDE EFFECTS AND DRUG INTERACTIONS
Hepatotoxicity is the main side effect.
Gynecomastia. This is due to the depletion of
cholesterol by interfering with cholesterol
biosynthesis in mammalian cells leading to low
levels of testosterone in men.
It is metabolized by CYP3A4 so administration
with CYP3A4 inducers such as phenytoin and
carbamazepine greatly reduce plasma levels of
ketoconazole.

it is a powerful inhibitor of CYP450 so
administration with drugs that are metabolized by
these enzymes greatly increases their plasma
levels leading to toxicities e.g. phenytoin and
cyclosporine.
Ketoconazole is used in treatment of oral thrush
and in shampoos and creams for treatment of
cutaneous candidiasis.
continued

.
Ketoconazole and amphotericin B should NOT be
used together, because the decrease in
ergosterol in the fungal membrane reduces the
fungicidal action of amphotericin B.

CLOTRIMAZOLE
IUPAC NAME . 1-(o-Chloro-,-diphenyl benzyl)imidazole
is a broad-spectrum antifungal drug that
is used topically for the treatment of tinea infections and
candidiasis
A 1% vaginal cream and tablets of 100 mg and 500 mg are available
for vulvovaginal candidiasis
Although clotrimazole is effective against various pathogenic yeasts
and is reasonably well absorbed orally, it causes severe
gastrointestinal disturbances. It is also extensively protein bound
and, hence, is not considered optimally bioavailable. Clotrimazole
is not considered suitable for the treatment of systemic infections.

SYNTHESIS
It is synthesized by reacting 2-
chlorotriphenylmethylchloride with imidazole in
the presence of triethylamine

16
Clotrimazole Synthesis
Clotrimazole

ECONAZOLE
1-[2-[(4-Chlorophenyl)methoxy]-2-(2,4-dichlorophenyl)-
ethyl]-1H-imidazole (Spectazole) is a white crystalline nitric
acid salt of econazole. It is only slightly soluble in water
and most organic solvents.
Econazole is used as a 1% cream for the topical treatment
of local tinea infections and cutaneous candidiasis.

TRIAZOLES.
ITRACONAZOLE
IUPAC NAME: 4-[4-[4-[4-[(2,4-Dichlorophenyl)-2-
1H-1,2,4-triazol-1-ylmethyl]- 1,3-dioxolan-4-
yl]methoxy]phenyl]-1-piperazinyl]phenyl-2,4-
dihydro-2-(1-methylpropyl)-3H-1,2,4-triazo-3-one.
Unique member of azole- contains two triazole
moieties- a weakly basic 1,2,4-triazole and non-
basic 1,2,4-triazol-3-one

Triazole:
basic, binding toheme
part of 14α-
demethylase via N4
1,2,4-triazol-3-one:
N4in 1,2,4-triazol-3-one
hasno available lonepair
for coordination with
heme iron, no binding to
14α-demethylase
4
4
Not basic
Lone pair is involved
in resonance

ITRACONAZOLE CONTINUATION
Itraconazole is an orally active, broad-spectrum antifungal agent that has
become an important alternative to ketoconazole.
An acidic environment is required for optimum solubilization and oral
absorption of itraconazole .Food greatly enhances the absorption of
itraconazole, nearly doubling its oral bioavailability.
The 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.
Virtually none of the unchanged drug is excreted in the urine. Thus,
the dosage need not be adjusted in patients with renal impairment.
The terminal elimination half-life of itraconazole ranges from 24 to 40
hours.

The primary indications for itraconazole are for the treatment of systemic
fungal infections.
In general, itraconazole is more effective and better tolerated
than is ketoconazole. It is not hepatotoxic and does not cause adrenal or
testicular suppression in recommended therapeutic doses.
Nonetheless, itraconazole can inhibit cytochrome P450 oxidases involved in
drug and xenobiotic metabolism and is known to increase plasma levels of
the antihistaminic drugs terfenadine and astemizole.

DIFFERENCE BETWEEN KETOCONAZOLE AND ITRACONAZOLE.
Triazole
Imidazole
extensively metabolised toinactive
metabolites (N-deacetylation )
Longerhalf-life
Active hydroxy-
metabolite(omega-1
hydroxylation)

Itraconazole Ketoconazole
Better tolerated, nothepatotoxic, no
anti-androgenic effects.
Generally triazole derivatives
are safer
Inhibits the synthesis of cholesterol
and other steroid hormones ( anti-
androgenic effects (loss of libido
gynecomastia).
More effective, Broad spectrum
antifungal agent thanketoconazole
Also effective against Aspergillus
infections.
Generally triazole derivatives
are more active
not effective against Aspergillus.
Longer half-life (20-30 h) than
ketoconazole (6-9 h), activehydroxy-
metabolite
Ketoconazole is extensively
metabolized to the inactive
deacetylated product

FLUCONAZOLE
IUPAC NAME -2,4-difluoro-,-bis(1H-1,2,4-triazol-1-
ylmethyl)benzyl alcohol.
It has broad-spectrum antifungal properties
It is suitable for both oral and intravenous administration
It can cross the BBB
Effective against cryptococcus neoformans.
Drug of choice for cryptococcal meningitis
It has a long half life 27-34 hrs.
It is a weak inhibitor of CYP3A4 but strong inhibitor of
CYP2C9 hence increasing availability of warfarin.
It has limited water solubility so its formulated as a pro-
drug.

FLUCONAZOLE CONTINUED
The oral bioavailability of fluconazole is excellent. Apparently,
the presence of two weakly basic triazole rings in the molecule
confers sufficient aqueous solubility to balance the lipophilicity
of the 2,4-difluorophenyl group.
The oral absorption of fluconazole is not affected
by alteration in gastrointestinal acidity or the presence
of food.
Plasma protein binding of fluconazole is less than 10%; the drug
is efficiently removed from the blood by hemodialysis

Fluconazole is recommended for the treatment and prophylaxis of
disseminated and deep organ candidiasis.
It is also used to control esophageal and oropharyngeal candidiasis.
Because of its efficient penetration into CSF, fluconazole is an agent of
choice for the treatment of cryptococcal meningitis

VORICONAZOLE
It is a fluconazole analog that has a broader
spectrum of activity.
Active against aspergillus and fluconazole
resistant strains of candida and cryptococcus
neoformans.
Extensively metabolized by CYP450 enzymes.
Inhibitor of CYP2C19, CYP2C9, CYP3A4 leading to
many drug interactions.

POSACONAZOLE
used to treat invasive infections by Candida species and
Aspergillus species in severely immunocompromised patient
Posaconazole primarily circulates as the parent compound in
plasma. Of the circulating metabolites, the majority are
glucuronide conjugates formed via UDP glucuronidation (phase
2 enzymes).
Posaconazole does not have any major circulating oxidative
(CYP450 mediated) metabolites.
THIS IS WHY IT HAS FEWER DRUG INTERACTIONS COMPARED TO
KETOCONAZOLE AND ITRACOINAZOLE .

Ketoconazole
Itraconazole Other drugs
-
Drug – Drug Interactions
PhaseII (conj.)
CYP450 (phase I) CYP3A4
Posaconzaole
direct phase
II metabolism
no competition
with other
drugs for the
CYP450

ALLYL AMINES
The drugs in this group are strictly terbinafine and
naftifine
Tolnaftate and butenafine have the same mechanism of
action as allyl amines so are classified under this group.
They have a limited spectrum of activity so are used only
in treatment of dermatophytes of nails and skin.

ALLYL AMINES
MOA
They interfere with an early step in ergosterol
biosynthesis, namely, the epoxidation of squalene
catalyzed by squalene epoxidase.
Squalene epoxidase forms an epoxide at the
C2–C3 position of squalene.
Opening of the epoxide under acid catalysis yields a
carbocation that initiates the "squalene zipper” reaction
that forms the steroid nucleus.
Inhibition of squalene epoxidase shuts down the
biosynthesis of ergosterol and causes an accumulation of
squalene, which destabilizes the fungal cell membrane

SAR
The structural requirements for potent activity are represented in
the broadest sense by two lipophilic domains linked to a central
polar moiety by spacers of appropriate length; for good activity.
The polar moiety is a tertiary amine, and one of the lipophilic
domains consists of a bicyclic aromatic ring system such as
naphthalene or benzo[blthiophene

NAFTIFINE
IUPAC NAME : N-Methyl-N-(3-phenyl2-propenyl)-1-
naphthalenemethanamine
Hydrochloride.
It is available only orally because it undergoes extensive
first pass effect.

TERBINAFINE
IUPAC NAME; E-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-
methyl-1-naphthalene-methanamine hydrochloride
It is available in both topical and oral forms.
Terbinafine hydrochloride is available in a 1% cream
for topical administration for the treatment of tinea
pedis, tinea corporis, and tinea cruris.
Terbinafine is more potent than naftifine and has
also
demonstrated oral activity against onychomycosis.
Terbinafine is metabolized by CYP450 enzymes, CYP2C9,

BUTENAFINE AND TOLNAFTATE
They are only available as topical preparations.
Unlike terbinafine, tolfonate spectrum is restricted primarily to
dermatophytes; the lack of effect on Candida spp. is attributed to poor
penetration of the cell envelope . Consequently, it is not used in the
treatment of systemic disease and its pharmacokinetic properties
dictate topical administration for the treatment of skin infections, such
as athlete's foot, where cure rates are around 80%.

MORPHOLINES
The compound inhibits both A14 reductase and A7-As
isomerase.
Antifungal activity is attributable primarily to inhibition of the
former, which is an essential enzyme in S. cerevisiae (129). The
toxicity of amorolfine precludes its systemic use.

FLUCYTOSINE(5-Fluorocytosine)
IUPAC NAME; 4-amino-5-fluoro-2(1H)-pyrimidinone,
2-hydroxy-4-amino-5-fluoropyrimidine

MOA
Once inside the cell, 5-fluorocytosine is deaminated in a reaction catalyzed
by cytosine deaminase to yield 5-fluorouracil(5-FU). 5-Fluorouracil is the active
metabolite of the drug.
5-Fluorouracil enters into pathways of both ribonucleotide and
deoxyribonucleotide synthesis.
The fluororibonucleotide triphosphates are incorporated into RNA, causing
faulty RNA synthesis. This pathway causes cell death. In the
deoxyribonucleotide series, 5-fluorodeoxyuridine monophosphate (F-dUMP)
binds to 5,10-methylenetetrahydrofolic acid, interrupting the one-carbon pool
substrate that feeds thymidylate synthesis. Hence, DNA synthesis is blocked.

SIDE EFFECTS
• Leukopenia
• Thrombocytopenia
NB; The hematological toxicities may result from the conversion
of flucytosine to antimetabolite 5-flurouracil by bacteria in the
host.

Resistance is very common.
One strategy used to decrease resistance and to prolong the effect of 5-
FC is to administer it with the polyene antibiotic amphotericin B. The
antibiotic creates holes in the fungal cell membrane, bypassing the
transport step and allowing 5-FC to enter.
Additionally, a lower dose of 5-FC can be used, preventing resistance by
other mechanisms for a longer period.

GRISEOFULVIN
IUPAC NAME; 7-chloro-2,4,6-trimethoxy-6,-methylspiro[benzofuran-
2(3H)-1-[2]cyclohexene]-3,4-dione.
The compound is a white, bitter, heat-stable powder or crystalline solid
that is sparingly soluble in water but soluble in alcohol and other
nonpolar solvents.
It is very stable when dry.
The oral bioavailability of griseofulvin is very poor. The compound is
highly lipophilic with low water solubility

continuation
It is a fungistatic
It works by reversible dissolution of the mitotic spindle apparatus,
probably by binding with the tubulin dimer that is required for
microtubule assembly.
Used in the treatment of skin and nail infections

SAR
The variations in the griseofulvin structure cover five
positions, namely the 4, 5, 2′, 3′, and 4′ positions.
Modification of the 4 and 5 positions affords inactive
molecules.
The enol ether must be at the 2′ position, and the 4′ position
needs to be sp2 hybridized.
The most active analogues were the 2′-benzyloxy and 2′-(4-
methylbenzyloxy) analogues as well as the oxime of the
former with a 25-fold increase of activity compared to
griseofulvin.

SARS
Structural features common to these lipopeptides include a
cyclic peptide composed of six amino acids, one of which (an
ornithine) is acylated at the a-N with a fatty acid containing
14-18 carbons.
The peptide is cyclized by an aminal linkage connecting 3-
hydroxy-4-methylproline to the &amino group of
dihydroxyornithine.
This group is readily cleaved at basic pH, resulting in ring
opening and complete loss of antifungal activity.

MOA
They act as noncompetitive inhibitors of (1,3)--d-glucan
Synthase, an enzyme complex that forms stabilizing glucan
polymers in the fungal cell wall.

TOPICAL AGENTS FOR DERMATOPHYTOSES

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