medicinal chemistry of antifungal agents
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ANTIFUNGAL DRUGS
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Mr.Ganesh D.Mote
Monera is a kingdom that contains unicellular organisms with a
prokaryotic cell organization, (having no nuclear membrane), such as
bacteria
eukaryotic one-celled living organisms distinct from multicellular plants and animals: protozoa, slime molds, and eukaryotic algae taxonomic kingdom
comprising all living or extinct animals
Plants, also called green plants (Viridiplantae in Latin), are living multicellular organisms of thekingdom Plantae.
1. OVER VIEW OF FUNGAL
Lack chlorophyll, leaves, true stems, and roots, reproduce by spores, and live as saprotrophs or parasites 2
Mr.Ganesh D.Mote
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THE FUNGI KINGDOMMycology - the study of fungi
fungi - singular
fungus - plural
1) fungi are eukaryotic
•they have a nuclei & mitochondria
2) they are heterotrophs•they depend on other organisms for food
3) they are multicellular
4) they cannot move on their own
4 Main Characteristics of Fungi
1. OVER VIEW OF FUNGAL
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Major Types of Mycosessuperficial cutaneous subcutaneous systemicopportunistic
1. OVER VIEW OF FUNGAL INFECTION
Mr.Ganesh D.Mote
PATHOGENIC FUNGAI
1. CANDIDA
2. ASPERGILLUS
3. CRYPTOCOCCUS
4. HISTOPLASMA
5. PNEUMOCYSTIS
6. STACHYBOTRYS
7. MICROSPORUM
8. TRICHOPHYTON
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2. TYPES OF FUNGAL INFECTIONS
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1). CANDIDACandida species cause infections in individuals with deficient immune systems. Th1-type cell-mediated immunity (CMI) is required for clearance of a fungal infection.
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2. TYPES OF FUNGAL INFECTIONS
CANDIDA INFEC TIONS
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2). ASPERGILLUS•The most common pathogenic species are Aspergillus fumigatus and
Aspergillus flavus. Aspergillus flavus produces aflatoxin which is both a
toxin and a carcinogen and which can potentially contaminate foods such
as nuts.
•Aspergillus fumigatus and Aspergillus clavatus can cause allergic
disease. •Some Aspergillus species cause disease on grain crops,especially
maize,and synthesize mycotoxins including aflatoxin.
•Aspergillosis is the group of diseases caused by Aspergillus. The
symptoms include fever, cough, chest pain or breathlessness.
Usually, only patients with weakened immune systems or with other lung
conditions are susceptible.
2. TYPES OF FUNGAL INFECTIONS
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2. TYPES OF FUNGAL INFECTIONS
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Aspergillus fumigatus Infection
Aspergillus flavusInfection
2. TYPES OF FUNGAL INFECTIONS
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3. CRYPTOCOCCUS•Cryptococcus neoformans can cause a severe form of meningitis
and meningo-encephalitis in patients with HIV infection and AIDS. The
majority of Cryptococcus species live in the soil and do not cause
disease in humans.
• Cryptococcus neoformans is the major human and animal pathogen.
Cryptococcus laurentii and Cryptococcus albidus have been known to
occasionally cause moderate-to-severe disease in human patients with
compromised immunity.
•Cryptococcus gattii is endemic to tropical parts of the continent of
Africa and Australia and can cause disease in non-
immunocompromised people.
2. TYPES OF FUNGAL INFECTIONS
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11 CRYPTOCOCCUS INFECTION
2. TYPES OF FUNGAL INFECTIONS
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12CRYPTOCOCCUS INFECTIONS
2. TYPES OF FUNGAL INFECTIONS
Mr.Ganesh D.Mote
4. HISTOPLASMA
Histoplasma capsulatum can cause
histoplasmosis in humans, dogs and
cats.
Infection is usually due to inhaling
contaminated air.
2. TYPES OF FUNGAL INFECTIONS
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2. TYPES OF FUNGAL INFECTIONS
HISTOPLASMA INFECTIONSMr.Ganesh D.Mote
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5. PNEUMOCYSTIS
Pneumocystis jirovecii
(or Pneumocystis carinii) can
cause a form of pneumonia
in people with weakened
immune systems, such as
premature children, the
elderly, and AIDS patients.
2. TYPES OF FUNGAL INFECTIONS
Mr.Ganesh D.Mote
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2. TYPES OF FUNGAL INFECTIONS
PNEUMOCYSTISMr.Ganesh D.Mote
6. STACHYBOTRYS
Stachybotrys chartarum or "black mold"
can cause respiratory damage and
severe headaches. It frequently occurs
in houses in regions that are chronically
damp.
2. TYPES OF FUNGAL INFECTIONS
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7. MICROSPORUM
Microsporum canis is a fungus that can cause tinea capitis in humans, and simple ringworm in pets.
2. TYPES OF FUNGAL INFECTIONS
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MICROSPORUM CANIS INFECTION
2. TYPES OF FUNGAL INFECTIONS
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The fungus genus Trichophyton rubrum is characterized by the development of both smooth-walled macro- and microconidia.
Macroconidiaare mostly borne laterally directly on the hyphae or on short pedicels, and are thin- or thick-walled, clavate to fusiform, and range from 4 to 8 by 8 to 50 μm in size
8. TRICHOPHYTON2. TYPES OF FUNGAL INFECTIONS
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2. TYPES OF FUNGAL INFECTIONS
TRICHOPHYTON INFECTION21
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5.CLASSIFICATION
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Chemical classification with structure
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1.Antifunal antibioticsa.Polyene antibiotics
b.Other antifungal antibiotics
griseofulvin
2.Allyl amines
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terbinafine Tolnaftate
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3. CHEMICAL STRUCTURES AZOLE ANTIFUNGAL DRUGS
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5.CLASSIFICATION OF ANTIFUNGAL
Con…
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6.SITES OF ACTION OF COMMON ANTIFUNGAL DRUGS
Con…
POLYENES
IMIDAZOLESTRIAZOLE
ALLYLAMINES
OTHER
GLUCAN SYNTHASE INHIBITORS
BIND TO ERGOSTEROL AND FORM PORES (CHANNELS)
Mr.Ganesh D.Mote
6.SITES OF ACTION OF COMMON ANTIFUNGAL DRUGS
ALLYLAMINES
IMIDAZOLESTRIAZOLE
POLYENES
28GLUCAN
SYNTHASE INHIBITORS
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6.SITES OF ACTION OF COMMON ANTIFUNGAL DRUGS
Mr.Ganesh D.Mote
FLUCYTOSINE
IMIDAZOLES
TRIAZOLES
POLYENES
CANDINS
GRISEOFULVIN
OTHERS
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7. ANTI FUNGAL DRUGS MECHANISAM
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8.MECHANISM OF AMPHOTERICIN B
Several amphotericin B molecules bind to ergosterol in the plasma membranes of sensitive fungal cells.
There, they form pores (channels) that require hydrophobic interactions between the lipophilic segment of the polyene antibiotic and the sterol.
The pores disrupt membrane function, allowing electrolytes (particularly potassium) and small molecules to leak from the cell, resulting in cell death.
Mr.Ganesh D.Mote
Flucytosine enters fungal cells via a cytosine-specific permease an enzyme not found in mammalian cells.
Flucytosine is then converted by a series of steps to 5-fluorodeoxyuridine 5'-monophosphate.
This false nucleotide inhibits thymidylate synthase, thus depriving the organism of thymidylic acid an essential DNA component.
Note: [Amphotericin B increases cell permeability, allowing more 5-FC to penetrate the cell. Thus, 5-FC and amphotericin B are synergistic.]
9.MECHANISM OF FLUCYTOSINE
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10.MECHANISM OF KETOCONAZOLE
Azoles are predominantly fungistatic. They inhibit C-14 α-demethylase (a cytochrome P450 enzyme), thus blocking the demethylation of lanosterol to ergosterol the principal sterol of fungal membranes.
This inhibition disrupts membrane structure and function and, thereby, inhibits fungal cell growth.
[Note:In addition to blocking fungal ergosterol synthesis, the drug also inhibits human gonadal and adrenal steroid synthesis, leading to decreased testosterone and cortisol production. In addition, ketoconazole inhibits cytochrome P450]
33 Dr.K.Saminathan.M.Pharm, M.B.A, Ph.DMr.Ganesh D.Mote
Terbinafine inhibits fungal squalene epoxidase, thereby decreasing the synthesis of ergosterol .
This plus the accumulation of toxic amounts of squalene result in the death of the fungal cell.
11.MECHANISM OF TERBINAFINE
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It is only fungistatic, and it causes a number of significant drug interactions.
Griseofulvin accumulates in newly synthesized, keratin-containing tissue, where it causes disruption of the mitotic spindle and inhibition of fungal mitosis .
12. MECHANISM OF GRISEOFULVIN
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13. SOME ADVERSE REACTIONS OF ANTIFUNGAL DRUGS
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14. SOME ADVERSE REACTIONS OF AMPHOTERICIN B.
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POLYENES
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IMIDAZOLES
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TRIAZOLE ALLYLAMINES
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Β-3-GLUCAN SYNTHASE INHIBITORS
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Griseofulvin Flucytosine
Dr.K.Saminathan.M.Pharm, M.B.A, Ph.DMr.Ganesh D.Mote
SAR OF AZOLE ANTIFUNGAL AGENTS1. 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.
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.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.
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Clotrimazole
Fluconazole
Mechanism action of squaline epoxidase(allyl amines and lanoseterol 14 ά demethylase inhibitor(Azoles derivatives)
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Synthesis of Ketoconazole
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Cl
Cl
C
O
CH2Br
2-bromo-1-(2,4-dichlorophenyl)ethanone
CH2OH
HC
H2C OH
OH
propane-1,2,3-triol
Cl
Cl
C CH2BrOO
CH2OH
(2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-
yl)methanol
C
O
Cl
Cl
Cl
COO
CH2COO
CH2
NN
Cl
Cl
COO
CH2
NN
H2C O SO2CH3
CH3SO3Cl
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1-(3,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanone
Cl C
O
H2C N
Cl
N
Cl CH
OH
H2C N
Cl
N
1-(3,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol
NaBH4
Cl
Cl
H2CBr
1-(bromomethyl)-2,4-dichlorobenzene
Synthesis of Miconazole
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2-Naphthol thiophosgene
N-methyl 3-toludine
O Cl
S
O-naphthalen-2-yl carbonochloridothioate
O N
S
CH3
CH3
O-naphthalen-2-yl methyl(m-tolyl)carbamothioate
Synthesis of Tolnaftate
Thank you
Mr.Ganesh D.Mote48
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