ANTIFUNGAL AGENTS

NAME: SK SURAJ
ROLL:38301921059
REGISTRATION NO. : 213830201910010
SUBJECT: MEDICINAL CHEMISTRY III
PAPER CODE: PT613
SESSION:2021-2025
CA2
DEPARTMENT: B.PHARM,3rd YEAR
(6th SEMESTER)
SEACOM PHARMACY COLLEGE
INTRODUCTION:
Fungi belong to a diverse group of organisms that includes yeasts, moulds and
dermatophytes. They are classified in a separate kingdom from animals, plants and
bacteria,and physiologically have most in common with animals. Most fungi live harmlessly
in the environment, especially in soil and decaying matter, but approximately 200 species can
cause disease in the human host.
Fungal infections are not usually serious in otherwise fit, healthy adults, but they can be
embarrassing and distressing. Very ill and immune-compromised patients are at risk of
serious fungal infections, especially if they have had multiple courses of antibiotics and have
undergone invasive procedures. Exogenous infection (cross-infection) caused by fungi can
occur from one patient to another at home and in healthcare settings.
More than 300,000 species of fungi have been identified, but most live harmlessly in the
environment where they play an important role in breaking down and recycling organic
material from dead animals and plants. Only a few species are pathogenic (able to cause
disease). Some fungi, for example yeasts, assume a very simple structure and exist as single
cells.
More complex forms display filamentous branching structures called hyphae. These can
become highly interwoven to form a mesh called a mycelium. A fungal infection is called a
mycosis, whereas mycology is the study of fungi. Fungal infections affecting the skin are
sometimes referred to as dermatophytic infections.

FUNGAL DISEASES:
The fungal kingdom includes yeasts, molds, rusts and mushrooms, Most fungi a saprophytic,
which means that they live on dead organic matter in the soil or on decaying of these fungi
can cause opportunistic infections if they are Into a human through wounds or by inhalation.
Some of these infections can be fatal. There are relatively few obligate animal parasites (ie,
microorganisms then younly live on mammalian hosts) among the fungi, although Candida
albicans is commonly found as part of the normal flora of the gastrointestinal tract and
vagina. The obligatory parasites are limites to dermatophytes that have evolved to live on/ in
the keratin-containing hair and skin of mammals, where they cause diseases such as
ringworm and athletes foot.
All fungi produce spores, which may be transported by direct contact or through the air
Although most topical fungal infections are readily treated, the incidence of life threatening
systemic fungal infections, including those caused by yeasts such as Condida albicans and
molds such as Aspergillus fumigans are increasing, and mortality remains high.

CLASSIFICATION OF ANTIBIOTICS:
(a) Antifungal antibiotics: Amphotericin-8, Nystatin, Natamycin, Griseofulvin.
(b) Synthetic Antifungal agents: Clotrimazole, Econazole, Butoconazole, Oxiconazole,
Tioconazole, Miconazole, Ketoconazole, Terconazole, Itraconazole, Fluconazole, Naftifine
hydrochloride, Tolnaftate.
Antifungal Antibiotics
The antifungal antibiotics make up an important group of antifungal agents. All of the
antibiotics are marked by their complexity. :
There are two classes of antifungal antibiotics
(a) Polyenes: Amphotericin-B, Nystatin, Natamycin.
(b) Griseofulvin
( a) Polyene Antibiotics:
A number of structurally complex antifungal antibiotics have been isolated from soil bacteria
of the genus Streptomyces. The compounds are similar, in that they contain a system of
conjugated double bonds in macrocyclic lactone rings. They contain the conjugated-ene
system of double bonds. Hence, they are called the polyene antibiotics.
The common features of the polyene antibiotics are:
(1) A series of hydroxyl groups on the acid-derived portion of the ring and
(2) A glycosidically linked deoxyaminohexose called mycosamine.The number of double
bonds in the macrocyclic ring differs also,
(3) Natamycin, the smallest macrocycle, is a pentene,
(4) Nystatin is a hexaene, and
(5) Amphotericin-B is a heptaene.
Mechanism of Action of Polyene Antibiotics:
Polyene antibiotics contain three-dimensional shape, a barrel-like non-polar structure capped
by a polar group (the sugar). They penetrate the fungal cell membrane components as false
membrane components, and bind closely with ergosterol, causing membrane disuption,
cessation of membrane enzyme activity, and loss of cellular constituents, specially K ions.
The drug is fungistatic at low concentrations and fungicidal at high concentrations. This
suggests that at low concentrations the polyenes bind to a membrane-bound enzyme
component, such as an ATPase.
Uses of Polyene Antibiotics:
The polyenes have no activity against bacteria, rickeitsia, or viruses, but they are highly
potent; broad-spectrum antifungal agents.
• Polyene antibiotics have activity against certain protozoa, such as Leishmania spp.
• They are effective against pathogenic yeasts, molds, and dermalophytes.
• In low concentrations polyenes antibiotics, in-vitro inhibit various species such as
Candida, Cryptococcus, Aspergilllus and Cephalosporium.
Amphotericin-B is the only polyene useful for the treatment of serious systemic infections.
The other polyenes are indicated only as topical agents for superficial fungal infections
 ❖ Drug Profile for Antifungal Antibiotics:

1.Amphotericin-B:

▪ Amphotericin-B is a polyene antifungal antibiotic isolated in 1956 and purified from the
fermentation beer of a soil culture of the actinomycete Streptomyces nodosus.
▪ As the name implies. Amphotericin-B is an amphoteric substance, with a primary amino
group attached to the mycosamine ring and a carboxyl group on the macrocycle.
▪ It acts by binding to ergosterol, an essential component of the fungal cell membrane thereby
causing depolarization of the membrane and altering cell membrane permeability. This leads to
leakage of important intracellular components, cell rupture, and eventually cell death.
▪ Uses:
▪ Parenteral Amphotericin-B has broad spectrum of activity and is indicated for the treatment
of severe, potentially life threatening fungal infections.
▪ Limited use of amphotericin-B is because of high risk of adverse reactions. Nearly 80% of
patients treated with amphotericin-8 develop nephrotoxicity.
▪ Fever headache, anorexia, gastrointestinal distress, muscle and joint pain are common.
▪ Pain at the site of injection and thrombophlebitis are frequent complications of intravenous
injection and thrombophlebitis are frequent complications of intravenous administration.

2.Nystatin:

▪ Nystatin is a polyene antifungal antibiotic. It can be used as topical and oral antifungal agent.
▪ It is isolated in 1951 from a strain of the actinomycete Streptomyces noursei
▪ The aglycone portion of nystatin is called as Nystatinolide, whereas glycone part is called as
mycosamine.
▪ It has activity against many species of yeast and candida albicans.

Uses:
▪ Nystatin is used for the treatment of local and gastrointestinal monilial infections caused by
Candida albicans and other Candida species.
▪ Nystatin is used largely to treat skin and oropharyngeal candidiasis.

3.Natamycin:

▪ Natamycin is a polyene antibiotic obtained from cultures of Streptomyces natalensis.

▪ It exerts its antifungal effects by binding to sterols in the fungal cell membranethereby
increasing membrane permeability. This leads to a leakage and loss of essential cellular
constituents.
▪ It is a smaller polyene and it is fungistatic and fungicidal within the same concentration
range.

Uses:
▪ Natamycin is used for a variety of fungal infections, mainly topically.
▪ It possesses in vitro activity against a number of yeasts and filamentous fungi, including
Candida, Aspergillas, Cephalosporium, Penicillium, and Fusarium spp.5% ophthalmic
suspensions are used for the treatment of fungal conjunctivitis, blepharitis, and keratitis.

Synthetic Antifungal Agents:

(a) Azole Antifungal Agents: The azoles are synthetic antifungal agents with unique
mechanism of action. They can be used to treat infections ranging from simple
dermatophytoses to life threatening, deep systemic fungal infections. They are effective
against most fungi that cause superficia infections of the skin and mucous membranes.
Mechanism of Action
The fungicidal effect of azoles is because of damage to the cell membrane with the loss of
essential cellular components such as potassium ions and amino acids, whereas the
fungistatic effects of azoles at low concentration have been associated with inhibition of
membrane-bound enzymes such as a cytochrome Pasa class enzyme, lanosterol and 14a-
demethylase.
Drug Profile for Azole Antifungal Agents:
1.Clotrimazole:

• It is chemically. 1-12-chlorophenyl)-diphenylmethylimidazole.
•It acts by inhibiting 140-demethylase, a microsomal cytochrome Pato-dependent enzyme,
which catalyzes conversion of lanosterol to ergosterol, an essential component of the fungal
cell wall, thus increases cellular permeability thereby resulting in leakage of cellular contents
and eventually inhibits fungal cell growth, causes cell lysis.

Uses:
Clotrimazole is a broad spectrum antifungal drug used topically for the treatment of tinea
infections and oral candidiasis.

2.Econazole:

•Econazole is an imidazole antifungal agent.

• It is chemically, 1-[2-[(4-chlorophenyl)methoxy)-2-(2,4-dichlorophenylethyl] imidazole.

Uses:
•Econazole is used topically in dermatomycoses.
•1% cream is used for the topical treatment of local tinea infections and cutaneous
candidiasis.
 •It also has some action against Gram-positive bacteria.

3. Butoconazole:

•It is chemically, 1-[4-(4-chlorophenyl)-2-(2,6 dichlorophenyl) sulfanylbutyl]imidazole.

•Mechanism of action is same as that of Clotrimazole.

Uses:-
•It is active against many dermatophytes and yeasts.
• It is used as its nitrate salt in gynaecology for treatment of vulvovaginal infections caused by
Candida species, particularly Candida albicans.
•It also contains antibacterial effects against some Gram-positive organisms.

4.Oxiconazole:

•Oxiconazole is a broad spectrum imidazole derivative with antifungal activity.

• It is chemically, (2)-1-(2,4-dichlorophenyl)-N-[(2,4-dichlorophenyl)methoxy)-2-imidazol-1-
yl-ethanimine. Mechanism of action is same as that of Clotrimazole.

Uses:
• Oxiconazole is used in cream, lotion and powder for the topical treatment of fungal skin
infections.
5.Ketoconazole:

•Ketoconazole is a synthetic derivative of phenylpiperazine with broad antifungal properties.

• It is chemically, 1-[4-(4-[[(25,4R)-2-(2,4-dichlorophenyl)-2-(imidazol-1-yl-methyl)-1,3-
dioxoloan -4-Y]phenyl]piperazin-1-y]ethenone.
Uses:-
❖ Ketoconazole is a fungicidal agents with a very broad spectrum of activity against many
fungal species and it is used for the treatment of superficial and systemic fungal infections.

6.Miconazole:-

•Miconazole is a synthetic derivative of imidazole with an antifungal activity.

•It chemically, 1-12-(2,4-dichlorophenyl)-2-1(2,4
dichlorophenyl)methoxylethyl]- imidazole.
•Mechanism of action is same as that of Clotrimazole.
Uses:-
•Miconazole is used in the treatment of candidal skin infections. It is intended for the treatment
of serious systemic fungal infections, such as candidiasis, coccidioidomycosis and
cryptococcosis.
•It is also used for the treatment of chronic mucocutaneous candidiasis and vaginal candidiasis.
 ❖ Drug Profile for Allylamines and Related Compounds:

1.Naftifine Hydrochloride:

❖ Naftifine hydrochloride is an allylamine derivate with synthetic broad-spectrum

activity.
❖ It is chemically, (E)-N-methyl-N-(naphthalen-1-yl-methyl)-3-phenylprop-2-en-1-
amine hydrochloride.
❖ It acts selectively by inhibiting the enzyme squalene 2,3-epoxidase, thereby inhibiting
the biosynthesis of sterol. This results in a decreased amount of sterols, especially
ergosterol which is the primary fungal membrane sterol, and a corresponding
accumulation of squalene in fungal cells.
Uses:
❖ 1% concentration of Naftifine hydrochloride in a cream and in a gel is used for the
treatment of ringworm ,athlete’s foot,and jock inch.

2.Tolnaftate:

•Tolnaftate is a thiocarbamate derivative with either fungicidal or fungistatic property.

•Tolnaftate is classified with the allylamine antimycotics.
•It is a selective, reversible and non-competitive inhibitor of membrane- bound
squalene-2,3- epoxidase, an enzyme involved in the biosynthesis of ergosterol.
Inhibition leads to the accumulation of squalene and a deficiency in ergosterol, an
essential component of fungal cell walls, thereby increasing membrane permeability,
disrupting cellular organization and causing cell death.
Uses:
 •Tolnaftate is a thioester of ẞ-naphthol, is fungicidal against dermatophytes, such as
Trichophyton, Microsporum, and Epidermophyton spp, that cause superficial tines
infections.

• It is It is formulated into preparations intended to be used with artificial fingernails to

counteract the increased chance of ringworm of the nail beds.
❖ SYNTHESIS OF MICONAZOLE: