Medicinal Chemistry-III (BP601T) Anti fungal drug

1. Medicinal
Chemistry-III
(BP601T)
Chemistry of Anti-fungal Drug
Medicinal Chemistry-III (BP601T)

2. Chemistry of Anti-fungal Drug
Raj K. Prasad (Gold Medalist), M. Pharm.
(Pharmaceutical Chemistry)
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3. Antifungal drugs
Antifungal drugs can be divided into polyenes,
imidazole and triazole derivatives, allylamines, and
others.
The polyenes (nystatin, amphotericin B, natamycin)
bind with sterols in the fungal cell wall, principally
ergosterol.
This causes the cell’s contents to leak out and the cell
dies.
Human (and other animal) cells contain cholesterol
rather than ergosterol so are much less susceptible.
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4. Antifungal drugs
The imidazole and
triazole groups of
antifungal drugs
Imidazoles:
Miconazole,
Ketoconazole,
Clotrimazole,
Econazole,
Mebendazole,
Butoconazole,
Fluconazole
Inhibit the enzyme cytochrome P450. 14α-
demethylase.
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5. Classification Based on Chemical Structure
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6. Polyene Antifungal drug
The 26-membered–ring
polyenes, such as
natamycin, form one group,
whereas the 38- membered
macrocycles, such as
amphotericin B and nystatin,
form the other group.
Also common to the
polyenes are-
a series of hydroxyl groups
on the acid-derived portion
of the ring and
a glycosidically linked
deoxyaminohexose called
mycosamine.
The 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.
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7. AMPHOTERICIN-B
Amphotericin B is an amphoteric substance,
with a primary amino group attached to the
mycosamine ring and a carboxyl group on the
macrocycle.
amphotericin B forms salts with both acids and
bases.
The drug cannot cross the blood–brain barrier
and must be administered intrathecally for
treatment of fungal infections of the CNS.
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8. Uses
Amphotericin B remains the primary drug
for treating severe, acute systemic fungal
infections.
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9. NYSTATIN
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10. Chemistry
 The aglycone portion of nystatin is called
nystatinolide.
 It consists of a 38-membered macrolide lactone ring
containing single tetraene and diene moieties
separated by two methylene groups.
 The aglycone also contains eight hydroxyl groups,
one carboxyl group, and the lactone ester
functionality.
 The entire compound is constructed by linking the
aglycone to mycosamine.
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11. Uses
It is used for preventing
and treating candida
infections of the skin and
mucous membranes.
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12. NATAMYCIN R A J K . P R A S A D 1 2

13. Chemistry of 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.
Natamycin is a polyene antibiotic obtained from cultures of Streptomyces
natalensis.
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14. Uses
• Natamycin is a drug for treating
superficial fungal infections, and it is
used only for ophthalmologic purposes.
• The drug is supplied as a 5% ophthalmic
suspension intended for the treatment of
fungal conjunctivitis, blepharitis, and
keratitis.
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15. GRISEOFULVIN
• It as an antibiotic obtained from the
fungus Penicillium griseofulvum.
• It was isolated originally as a “curling
factor” in plants.
• Griseofulvin is have a rare structure in
nature, that is a spiro compound.
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16. Mode of action:
Griseofulvin is a fungi-static
drug that 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.
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17. Uses
• It is used orally to treat
superficial fungal infections,
primarily fingernail and toenail
infections, but it does not
penetrate skin or nails if used
topically.
• It has been also used for a long
time for the systemically
delivered treatment of
refractory ringworm infections
of the body, hair, nails, and feet
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18. STRUCTURE–
ACTIVITY
RELATIONSHIPS
(SAR)
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19. STRUCTURE–ACTIVITY
RELATIONSHIPS (SAR)
 The large nonpolar portion of these molecules
mimics the nonpolar steroidal part of the substrate
for lanosterol 14α-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.
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20. STRUCTURE–ACTIVITY
RELATIONSHIPS (SAR)
• 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.
• Only 2, and/or 2,4 substitution yields effective azole
compounds.
•
• 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.
• Substitution at other positions of the ring yields
inactive compounds.
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21. CLOTRIMAZOL
E
 Clotrimazole is an imidazole derivative because of
the presence of an imidazole ring in its structure.
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22. CLOTRIMAZOLE
 It is a weak base that can be solubilized by dilute
mineral acids. It is believed that, like miconazole,
econazole, and other “pure” representatives of the
imidazole class, it also inhibits the biosynthesis of
ergosterin in the cytoplasmatic membrane of fungi.
 In terms of pharmacological action, clotrimazole is
very similar to miconazole. It has a broad spectrum
of antifungal activity.
 It is effective with respect to dermatophytes, and it
also has an antimicrobial effect against streptococci
and staphylococci.
 Clotrimazole is highly stable, with a shelf life of more
than 5 years.
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23. BUTOCONAZOLE Butoconazole is a fungostatic drug, and
it is formally classified as an imidazole,
but only because of the presence of an
imidazole ring in the structure.
It is believed that butoconazole, inhibits
the biosynthesis of estrosterin in the
cytoplasmatic membrane of fungi.
It is an extremely broad-spectrum
antifungal drug that is specifically
effective against C. albicans.
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24. Uses
 It is effective for vaginal infections caused by
various types of candida. It is also used only
externally and vaginally.
 It is supplied as a vaginal cream containing 2%
of the salt.
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25. 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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26. TIOCONOZOLE
 It is used for the
treatment of
vulvovaginal
candidiasis. A vaginal
ointment containing
6.5% of the free base is
available.
 Tioconazole is more effective against Torulopsis glabrata
than are other azoles.
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27. MICONAZOLE
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28. Synthesis
 It is synthesized from 2,4-dichlorophenacylbromide,
which is reacted with imidazole to make 1-(2,4-
dichlorobenzoylmethyl)-imidazole[2,4-dichloro-ω-(1-
imidazolyl)- acetophenone].
 Reducing the carbonyl group in this molecule with
sodium borohydride gives 1-(2,4-dichlorophenyl)-3-(1-
imidazolyl)-ethanol, and the hydroxyl group is alkylated
by 2,4- dichlorobenzylbromide using a powerful base
such as sodium hydride to make miconazole.
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29. Synthesis
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30. Uses
• ·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, such as
candidiasis, coccidioidomycosis,
cryptococcosis, petriellidiosis, and
paracoccidioidomycosis.
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31. KETOCONAZOLE
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32. Chemistry
 It is an imidazole antifungal, was the first orally active antifungal azole to be discovered.
 Ketoconazole is highly dependent on low stomach pH for absorption, and antacids or drugs that raise stomach
pH will lower the bioavailability of ketoconazole.
 Coadministration of ketoconazole with the hypnotic triazolam results in a 22-fold increase in triazolam’s area
under the curve (AUC)
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33. Uses
• It is used Ketoconazole’s clinical use
has become limited to topical
applications in a variety of dosage forms,
including creams, lotions, suppositories,
and shampoos.
• In combination with shampoo for
treating and preventing mycelial fungi,
seborrheic dermatitis, and dandruff.
• Ketoconazole has a broad spectrum of
antifungal activity, including many candida
infections.
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34. TERCONAZOLE
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35. MOA
The exact mechanism of its
action is unknown, although it
inhibits the action of the enzyme
lanosterol 1-demethylase of
cytochrome P-450 of sensitive
fungi (similar to other azols),
causing a reduction in the
amount of ergosterin, which is
necessary for the organisms to
construct membranes and to
retain the appropriate
permeability. R A J K . P R A S A D 3 5

36. Uses
 It is only used externally for treating vulvovaginal
candidoses and is not used systemically.
 It is available in creams containing 0.4% and 0.8% of
the free base.
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37. ITRACONAZOLE
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38. ITRACONAZOLE It is a P-glycoprotein inhibitor.
Itraconazole was, along with fluconazole,
one of the first triazoles introduced into
clinical use.
It is a unique member of the azole class that
contains two triazole moieties in its structure,
a weakly basic 1,2,4-triazole and a nonbasic
1,2,4-triazol-3-one.
Its bioavailability is influenced by food
and stomach pH, a strongly acidic pH
being required for good absorption.
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39. Uses
 It is used exclusively for the control of
vulvovaginal moniliasis caused by C. albicans and
other Candida species.
 Primary use for itraconazole are for the treatment
of systemic fungal infections including
blastomycosis, histoplasmosis (including patients
infected with human immunodeficiency virus
[HIV]).
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40. FLUCONAZOLE
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41. Chemistry
 It is a water soluble bis-triazole with
broad-spectrum antifungal properties.
 It 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.
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42. Uses
 Fluconazole has useful activity
against Coccidioides immitis, and is
often used to suppress the meningitis
produced by the fungus.
 Fungicidal concentrations are
achieved in nails, vagina and saliva;
penetration into brain and CSF is
good. Dose reduction is needed in
renal impairment.
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43. NAFTIFINE
HYDROCHLORIDE
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44. chemistry
 Naftifine is the first representative of a
new class of antifungal drugs (naftifine,
terbinafine, amorolfine, butenafine)
classified as allylamines.
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45. Uses
• The widest use of naftifine is against
various tinea infections of the skin.
• It is supplied in a 1% concentration in
a cream and in a gel for the topical
treatment of ringworm, athlete’s foot,
and jock itch.
• Naftifine has shown efficacy for
treatment of ringworm of the beard,
ringworm of the scalp, and tinea
versicolor.
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46. TOLNAFTATE
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47. chemistry
 Tolnaftate has been shown to act as an
inhibitor of squalene epoxidase in susceptible
fungi, so it is classified with the allylamine
antimycotics.
 It is a thioester of β-naphthol, that is
fungicidal against dermatophytes, such as
Trichophyton, Microsporum, and
Epidermophyton.
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48. Synthesis
 It is synthesized by reacting equimolar
amounts of 2-naphthol and thiophosgene
to make a monosubstituted product of
thiophosgene, which is then reacted with
N-methyl-3-toluidine to give the desired
tolnaftate.
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49. uses
Tolnaftate is used as an external drug for moderate
dermatophyte infections (shingles), and it is not
effective for treating candida infections.
Tolnaftate is available in a concentration of 1% in
creams, powders, aerosols, gels, and solutions for the
treatment of ringworm, jock itch, and athlete’s foot.
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50. Thank You
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