SAR and Mechanism Of Action of Antifungal agents

1. ANTIFUNGALAGENTS
DR. MANJOOR AHAMAD SYED,
M.Pharm,Ph.D
Associate. Professor
Department of Medicinal Chemistry,
College of Public Health and Medical Sciences,
Mettu University, Mettu
Post Box No-318
Ethiopia.

2. ANTIFUNGAL AGENTS
These are the drugs or agents which are useful in the treatment of fungal infections are
known as antifungal agents.
OVER VIEW OF FUNGAL
Generally, the fungi have four main characteristics
 Fungi are Eukaryotic (They have a nucleus and mitochondria)
 They are Heterotrophs (They depends on other organisms for food)
 They are multicellular
 They cannot move on their own

3. Fungal Infection in Humans = Mycosis
 Major Types of Mycoses
 Superficial
 Cutaneous
 Subcutaneous
 Systemic
 Opportunistic
Symptoms vary from cosmetic to life threatening

4. Types of fungal infections
I. Mucocutaneous (superficial) infections:
a. Dermatophytes:
 Cause infection of skin, hair, and nails
e.g. Tinea capitis (scalp), tinea cruris (groin),
tinea pedis (foot), onychomycosis (nails).

5. b. Yeasts:
 Cause infections of
moist skin and mucous
membranes
e.g. Candida albicans causing
oral, pharyngeal, vaginal, &
bladder infections

6. II. Systemic mycoses:
 are fungal infections affecting
internal organs.
 It occurs in immunocompromized
patients e.g. cryptococcosis, and
aspergillosis (lung).

7. 1. Antifungal antibiotics
a. Polyenes – Amphotericin B and
Nystatin
b. Other antifungal antibiotics –
Griseofulvin
2. Azoles: -
a. Imidazole’s - Ketoconazole,
Clotrimazole, Miconazole.
b. Triazoles - Fluconazole, Itraconazole,
Voriconazole and Posaconazole
3. Allylamines – Tolnaftate, Terbinafine and
Naftifine.
4. β – 3-Glucan synthase inhibitor –
Capsofungin, Micafungin and Anidulafungin
5. Pyrimidine derivatives (Nucleosides) -
Flucytosine
6. Fatty acids and carboxylic acids – Sodium
caprylate, Triacetin, Undecylenic acid, Benzoic
acid, salicylic acid and Propionic acid
7. Phenols and their derivatives – Resorcinol
and clioquinol
Based on chemical structure and mechanism of action they are classified in to different types

8. Mechanism of Action

9. Antifungals can be
grouped into three classes
based on their site of action:
azoles, which inhibit the
synthesis of ergosterol (the
main fungal sterol);
polyenes, which interact
with fungal membrane
sterols physiochemically;
and 5-fluorocytosine, which
inhibits macromolecular
synthesis.

10. ANTIFUNGAL ANTIBIOTICS
POLYENES:
These compounds consist of macrolytic lactones with distinct hydrophilic,
lipophilic region along with conjugated -ene system of double bonds hence they
are called polyene antibiotics.
Based on number of double bonds they are classified in to different types
a. Tetraenes- Natamycin
b. Penta enes – Filipin
c. Hexaenes – Nystatin, Endomycin
d. Heptaenes – Amphotericin B and Candicidin

11. Mechanism of Action:
They have an affinity for sterols containing membranes, especially Ergosterol which is
a primary sterol for of the membrane of fungi and polyenes bind firmly to it, thereby
causing leakage of essential cell constituents and altering the membrane permeability,
which results in to cell death.
NYSTATIN
Nystatin is an antifungal medication that fights infections caused by fungus. Nystatin
when taken by mouth is used to treat yeast infections in the mouth or stomach. Oral
nystatin is not absorbed into your bloodstream and will not treat fungal infections in
other parts of the body or on the skin.

12. Common Side effects of Nystatin include:
Diarrhea, Nausea, Stomach pain or upset, Vomiting, Contact dermatitis, Stevens-
Johnson syndrome, Hypersensitivity reactions, Skin irritation or redness.
USES:
Nystatin, sold under the brand name Mycostatin among others, is an antifungal
medication. It is used to treat Candida infections of the skin including diaper rash,
thrush, esophageal candidiasis, and vaginal yeast infections. It may also be used to
prevent candidiasis in those who are at high risk.

13. AMPHOTERICINE B
USES:
Amphotericin B injection is used to treat serious and potentially life-threatening
fungal infections. Amphotericin B injection is in a class of medications called
antifungals. It works by slowing the growth of fungi that cause infection.
Common side effects may include:
Nausea, vomiting, stomach pain, diarrhoea, upset
stomach, loss of appetite, muscle or joint pain, headache,
ringing in your ears, pain, bruising, or swelling where the
medicine was injected, weight loss or flushing (warmth,
redness, or tingly feeling).

14. GRISEOFULVIN
(2S,6'R)-7-chloro-2',4,6-trimethoxy-6'-methyl-
3H-spiro[1-benzofuran-2,1'-cyclohexan]-2'-
ene-3,4'-dione.
Adverse Effects:
The more common side effects of griseofulvin can include: Rash, numbness or
tingling in your hands or feet, yeast infections in your mouth, stomach pain, diarrhea,
heartburn, nausea, vomiting.
USES:
Griseofulvin is an antifungal medicine that is used to treat infections such as
ringworm, athlete's foot, jock itch, and fungal infections of the scalp, fingernails, or
toenails. Griseofulvin may also be used for purposes not listed in this medication
guide.

15. AZOLES
Mechanism of action
Azoles inhibit fungal cytochrome P450
(14 α demethylase) necessary for
ergosterol synthesis, a major
component of fungal cell membrane.
This will alter membrane permeability
and disrupt its function.
They are broad spectrum fungistatic
against many dermatophytes and
candida.

16. N
N
Cl
1-[(2-chlorophenyl)(diphenyl)methyl]-1H-imidazole
Cl
Cl
+ N
H
N
-HCl
N
N
Cl
Clotrmazole
1-chloro-2-[chloro(diphenyl)methyl]benzene
1H-imidazole
CLOTRMAZOLE
Synthesis:
USES:
Clotrimazole is used to treat skin infections such as athlete's foot, jock itch, ringworm,
and other fungal skin infections (candidiasis).
Adverse Effects:
Some side effects can be serious. If
you experience any of the following
symptoms, stop
using clotrimazole and call your
doctor immediately:
•rash.
•hives.
•stomach pain.
•fever.
•chills.
•nausea.
•vomiting.
•foul-smelling vaginal discharge.

17. KETOCONAZOLE
O
O
N
N
Cl
Cl O
N N
O
ketoconazole should be used only when you cannot use other antifungal
medications. Ketoconazole can cause serious harm to your liver that may result in
liver transplant or cause death.
1-[4-(4-{[2-(2,4-Dichlorophényl)-2-(1H-imidazol-
1-ylméthyl)-1,3-dioxolan-4-yl] méthoxy} phényl)
-1-pipérazinyl] éthanone
Adverse Effects:
Common side effects of Nizoral include: nausea, vomiting, stomach pain, itching or
skin rash, headache, dizziness, breast swelling.
USES:
Ketoconazole is used to treat skin infections such as athlete's foot, jock itch,
ringworm, and certain kinds of dandruff. This medication is also used to treat a skin
condition known as pityriasis (tinea versicolor), a fungal infection that causes a
lightening or darkening of the skin of the neck, chest, arms, or legs.

18. MICONAZOLE
O
N
N
Cl
Cl
Cl
Cl
1-{2-[(2,4-dichlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl}-1H-imidazole
USES:
Vaginal miconazole is used to treat vaginal yeast infections in adults and children 12
years of age and older. Miconazole is in a class of antifungal medications called
imidazoles. It works by stopping the growth of fungi that cause infection.
Adverse effects:
Burning, stinging, swelling, irritation,
redness, pimple-like bumps, tenderness, or
flaking of the treated skin may occur. If any
of these effects persist or worsen, notify
your doctor or pharmacist promptly.

19. ITRACONAZOLE
USES:
Itraconazole tablets and capsules are used to treat fungal infections of the toenails.
Itraconazole oral solution (liquid) is used to treat yeast infections of the mouth and
throat or of the esophagus (tube that connects the throat to the stomach). Itraconazole
is in a class of antifungals called triazoles.
Adverse Effects:
Common side effects may include, headache,
dizziness, drowsiness, tiredness, increased blood
pressure, rash, itching, nausea, vomiting, stomach
pain, diarrhea, constipation, swelling, abnormal
liver function or blood tests, fever, muscle or joint
pain, unusual or unpleasant taste in your mouth.

20. FLUCONAZOLE
Adverse Effects:
Headache, diarrhea, nausea or upset stomach, dizziness, stomach pain, vomiting,
changes in the way food tastes, severe rash in people with lowered immunity.
USES:
Fluconazole is used to treat serious fungal or yeast infections, such as vaginal
candidiasis, oropharyngeal candidiasis (thrush, oral thrush), esophageal candidiasis
(candida esophagitis), other candida infections (including urinary tract infections,
peritonitis [inflammation of the lining of abdomen or stomach].
2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl) propan-2-
ol.

21. OH
N
N
N
N
N
N
F
F
Fluconazole
N
N
Cl
Clotrimazole
SAR OF AZOLE ANTIFUNGAL AGENTS
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. 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.

22. OH
N
N
N
N
N
N
F
F
Fluconazole
N
N
Cl
Clotrimazole
SAR OF AZOLE ANTIFUNGAL AGENTS
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.

23. OH
N
N
N
N
N
N
F
F
Fluconazole
N
N
Cl
Clotrimazole
SAR OF AZOLE ANTIFUNGAL AGENTS
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.

24. O
S
N
O-naphthalen-2-yl methyl(3-methylphenyl)thiocarbamate
OH Cl Cl
S
Thiophosgene
-HCl
O
S
Cl
+
N
H
-HCl
O
S
N
naphthalen-2-ol N,3-dimethylaniline Tolnaftate
TOLNAFTATE
Synthesis:
Adverse Effects:
Irritation of the treated skin may occur. If this effect persists or worsens, notify your doctor or
pharmacist promptly.
A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it
occurs. Symptoms of a serious allergic reaction may include: rash, itching/swelling (especially of the
face/tongue/throat), severe dizziness, trouble breathing.
Uses:
Tolnaftate is used to treat skin infections such as athlete's foot, jock itch, and
ringworm. It is an antifungal that works by preventing the growth of fungus.

25. Mechanism of Action:
Although the exact mechanism of action is not entirely known, it is believed
to inhibit squalene epoxidase, an important enzyme in the biosynthetic
pathway of ergosterol (a key component of the fungal cell membrane) in a
similar way to terbinafine.

26. CASPOFUNGIN
Mechanism of Action:
Caspofungin blocks the synthesis of β(1,3)-d-glucan of the fungal cell wall, by non-
competitive inhibition of the enzyme β(1,3)-d-glucan synthase. β(1,3)-d-Glucan is an
essential component of the cell wall of numerous fungal species.
Adverse Effects:
Nausea, vomiting, diarrhea, fever, flushing (warmth, redness, or tingly feeling of the
skin), headache, irritation at the injection site, skin rash or itching.
Uses:
Caspofungin is an antifungal medicine that fights infections caused by fungus.
Caspofungin is used to treat fungal infections of the stomach, lungs, esophagus, or
other internal body areas.

27. FLUCYTOSINE
4-Amino-5-fluoro-2(1H)-pyrimidinone
Adverse Effects:
Nausea, vomiting, loss of appetite, diarrhea, headache, dizziness, numbness, tingling,
or burning pain in your hands or feet, dry mouth or skin rash, Depression of bone
marrow at high doses, hair loss.
Uses:
Flucytosine is used to treat serious fungal infections in the body. It belongs to a class
of drugs known as antifungal drugs. It is often used with other medications. It works
by slowing the growth of certain types of fungus.

28. Mechanism of Action:
Flucytosine enters the fungal cell via
cytosine permease; thus, flucytosine is
metabolized to 5-fluorouracil within fungal
organisms. The 5-fluorouracil is extensively
incorporated into fungal RNA and inhibits
synthesis of both DNA and RNA. The
result is unbalanced growth and death of
the fungal organism.