medicinal chemistry of antifungal agents

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

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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

Mr.Ganesh D.Mote

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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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.


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Aspergillus fumigatus Infection

Aspergillus flavusInfection


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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.


Mr.Ganesh D.Mote

11 CRYPTOCOCCUS INFECTION


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12CRYPTOCOCCUS INFECTIONS


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4. HISTOPLASMA

Histoplasma capsulatum can cause

histoplasmosis in humans, dogs and

cats.

Infection is usually due to inhaling

contaminated air.


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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.


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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.


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7. MICROSPORUM

Microsporum canis is a fungus that can cause tinea capitis in humans, and simple ringworm in pets.


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MICROSPORUM CANIS INFECTION


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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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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)

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ALLYLAMINES

IMIDAZOLESTRIAZOLE

POLYENES

28GLUCAN

SYNTHASE INHIBITORS

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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

medicinal chemistry of antifungal agents

Health & Medicine