Antifungal Agents

Made by
Anjali Jain, SGSITS, Indore
 POLYENES
• 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 differ from the
erythromycin-type structure in that they are larger and contain the
conjugated -ene system of double bonds. Hence, they are called the
polyene antibiotics.
• The clinically useful polyenes fall into two groupings on the basis of
the size of the macrolide ring. The 26-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.
Cholesterol embedded in a lipid
bilayer
Ergosterol embedded in a lipid
bilayer
Amphotericin B-
• It 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.
• 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
Amphotericin B-
(1R,3S,5R,6R,9R,11R,15S,16R,17R,18S,19E,21E,23E,25E,27E,2
9E,31E,33R,35S,36R,37S)-33-[(2R,3S,4S,5S,6R)-4-amino-3,5-
dihydroxy-6-methyloxan-2yl]oxy-1,3,5,6,9,11,17,37-
octahydroxy-15,16,18-trimethyl-13-oxo-14,39
dioxabicyclo[33.3.1]nonatriaconta-19,21,23,25,27,29,31-
heptaene-36-carboxylic acid
• Nystatin- is a polyene antibiotic that was first isolated in 1951 from a
strain of the actinomycete Streptomyces noursei by Hazen and Brown.33 It
occurs as a yellow to light tan powder.
• Nystatin is very slightly soluble in water and sparingly soluble in organic
solvents.
• The compound is unstable to moisture, heat, and light.
• 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.
• The complete structure of nystatin has been determined by chemical
degradation and x-ray crystallography.
• Nystatin is a valuable agent for the treatment of local and
gastrointestinal monilial infections caused by C. albicans and other
Candida species.
• Natamycin (pimaricin; Natacyn) is a polyene antibiotic obtained from
cultures of Streptomyces natalensi.
• 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. Like the other polyene antibiotics,
natamycin is amphoteric.
• 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, whereas the 38-
membered–ring polyenes cause potassium leakage at low,
fungistatic concentrations and cell lysis at high, fungicidal
concentrations.
• The smaller polyenes are fungistatic and fungicidal within the same
concentration range.
• Griseofulvin- was first reported in 1939 by Oxford et al.38 as an
antibiotic obtained from the fungus Penicillium griseofulvum. It was
isolated originally as a “curling factor” in plants.
• Application of extracts containing the antibiotic to fungus-infected leaf
parts caused the leaf to curl up.
• The drug has been used for many years for its antifungal action in
plants and animals. In 1959, griseofulvin was introduced into human
medicine for the treatment of tinea infections by the systemic route.
Synthetic Antifungal-
Clotrimazole
1-(o-Chloro-,-diphenylbenzyl)imidazole
 Econazole Nitrate
1-[2-[(4-Chlorophenyl)methoxy]-2-(2,4-dichlorophenyl)- ethyl]-1H-imidazole
 Butoconazole Nitrate
1-[4-(4-Chlorophenyl)-2-[(2,6-dichlorophenyl)-thio]butyl]- 1H-imidazole
 Oxiconazole Nitrate
(Z)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanoneO-[2,4
dichlorophenyl)methyl]oxime mononitrate
 Tioconazole
1-[2-[(2-chloro-3-thienyl)methoxy]2-(2,4-dichlorophenyl)- ethyl]-1H-imidazole
 Miconazole Nitrate
1-[2-(2,4-Dichlorophenyl)-2-[2,4-dichlorophenyl]- methoxy]ethyl]-1H-
imidazole mononitrate
 Ketoconazole
1-Acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2(1H-imidazole-1- ylmethyl)-
1,3-dioxolan-4-yl]methoxy]phenyl]piperazine
 Terconazole
cis-1-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-
dioxolan-4-yl)methoxy]phenyl]-4-(1 methylethyl)piperazine
 Itraconazole
4-[4-[4-[4-[[2-(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- triazol-3-one
 Fluconazole
-(2,4-Difluorophenyl)--(1H-1,2,4-triazol-1-ylmethyl)- 1H-1,2,4-triazole-1-
ethanol or 2,4-difluoro-,-bis(1H-1, 2,4-triazol-1-ylmethyl)benzyl alcohol
Tolnaftate- also known by its IUPAC name, NAFTIFINE-
O-2-Naphthyl methyl(3-
methylphenyl)thiocarbamate
Anti- Protozoal
• Protozoal diseases are highly prevalent in tropical Third World
countries, where they infect both human and animal populations,
causing suffering, death, and enormous economic hardship.
• Malaria, amebiasis, giardiasis, trichomoniasis, toxoplasmosis, and, as a
direct consequence of the AIDS epidemic, P. carinii pneumonia (PCP).
• In some areas with temperate climates in which sanitation is poor, the
prevalence of amebiasis has been estimated to be as high as 20% of
the population.
• The causative organism, Entamoeba histolytica, can invade the wall of
the colon or other parts of the body (e.g., liver, lungs, skin).
• An ideal chemotherapeutic agent would be effective against both the
intestinal and extraintestinal forms of the parasite
• Amebicides that are effective against both intestinal and
extraintestinal forms of the disease are limited to the somewhat
toxic alkaloids emetine and dehydroemetine, the nitroimidazole
derivative metronidazole, and the antimalarial agent chloroquine.
• A second group of amebicides that are effective only against
intestinal forms of the disease includes the aminoglycoside
antibiotic paromomycin, the 8-hydroxyquinoline derivative
iodoquinol, the arsenical compound carbarsone, and diloxanide.
• Other protozoal species that colonize the intestinal tract and cause
enteritis and diarrhea are Balantidium coli and the flagellates, G.
lamblia and Cryptosporidium spp. Balantidiasis responds best to
tetracycline.
• Metronidazole and iodoquinol may also be effective. Giardiasis may
be treated effectively with furazolidone, metronidazole, or the
antimalarial drug quinacrine.
• Trichomoniasis, a venereal disease caused by the flagellated
protozoan T. vaginalis.
• Although it is not generally considered serious, this affliction can
cause serious physical discomfort. Oral metronidazole provides
effective treatment against all forms of the disease. It is also used to
eradicate the organism from asymptomatic male carriers.
• P. carinii is an opportunistic pathogen that may colonize the lungs of
humans and other animals and, under the right conditions, can cause
pneumonia. The organism has long been classified as a protozoan, but
recent RNA evidence suggests that it may be more closely related to
fungi.
• At one time, occasional cases of PCP were known to occur in premature,
undernourished infants and in patients receiving immunosuppressant
therapy. The situation changed with the onset of the AIDS epidemic.
• It is estimated that at least 60% and possibly as high as 85% of patients
infected with HIV develop PCP during their lifetimes.
• The combination of the antifolate trimethoprim and the sulfonamide
sulfamethoxazole constitutes the treatment of choice for PCP. Other
effective drugs include pentamidine, atovaquone, and a new
antifolate, trimetrexate.
• Toxoplasma gondii is an obligate intracellular protozoan that is best
known for causing blindness in neonates. Toxoplasmosis, the
disseminated form of the disease in which the lymphatic system,
skeletal muscles, heart, brain, eye, and placenta may be affected, has
become increasingly prevalent in association with HIV infection. A
combination of the antifolate pyrimethamine and the sulfa drug
sulfadiazine constitutes the most effective therapy for toxoplasmosis.
• Various forms of trypanosomiasis, chronic tropical diseases caused
by pathogenic members of the family Trypanosomidae, occur both in
humans and in livestock.
The principal disease in humans, sleeping sickness, can be broadly
classified into two main geographic and etiological groups: African
sleeping sickness caused by Trypanosoma gambiense (West African),
Trypanosoma rhodesiense (East African), or Trypanosoma congolense;
and South American sleeping sickness (Chagas disease) caused by
Trypanosoma cruzi. Of the various forms of trypanosomiasis, Chagas
disease is the most serious and generally the most resistant to
chemotherapy. Leishmaniasis is a chronic tropical disease caused by
various flagellate protozoa of the genus Leishmania. The more common
visceral form caused by Leishmania donovani, called kala-azar, is similar
to Chagas disease. Although these diseases are widespread in tropical
areas of Africa and South and Central America, they are of minor
importance in the United States, Europe, and Asia.
• Chemotherapy of trypanosomiasis and leishmaniasis remains
somewhat primitive and is often less than effective.
• In fact, it is doubtful that these diseases can be controlled by
chemotherapeutic measures alone, without successful control of the
intermediate hosts and vectors that transmit them.
• Heavy metal compounds, such as the arsenicals and antimonials,
are sometimes effective but frequently toxic.
• The old standby suramin appears to be of some value in long- and
short-term prophylaxis.
• The nitrofuran derivative nifurtimox may be a major asset in the
control of these diseases, but its potential toxicity remains to be
fully determined
 Metronidazole
2-Methyl-5-nitroimidazole-1-ethanol
• Reactive intermediate formed in the microbial reduction of the 5-
nitro group of metronidazole covalently binds to the DNA of the
microorganism, triggering the lethal effect.89 Potential reactive
intermediates include the nitroxide, nitroso, hydroxylamine, and
amine. The ability of metronidazole to act as a radiosensitizing agent
is also related to its reduction potential.
 Diloxanide
Furamide, or eutamide, is the 2-furoate ester of 2,2-dichloro 4-hydroxy-
N-methylacetanilide.
α,α-dichloroacetamides