IPS1 - Medicinal Chemistry - Anti-fungal Agents

Proverbs 16:3

Mycology

____ - is the study of fungi

Propionic acid

[Topical Antifungal Agents]

______ -

• non-irritating and non-toxic

• present in perspiration or sweat

0.01%

PROPIONIC ACID around _____ % is fungicidal 

• Zinc propionate

• Sodium caprylate

• Zinc caprylate

Salt form of propionic acid [3]

Zinc propionate

[Salt form of Propionic Acid ]

____- is used as fungicide on adhesive tapes

Sodium caprylate

[Salt form of Propionic Acid ]

____- are cream-colored granules used topically to treat superficial dermatomycoses

Zinc caprylate

[Salt form of Propionic Acid ]

____-  is a fine white powder and a topical fungicide and unstable to moisture

Undecylenic acid

[Topical Antifungal Agents]
10-undecenoic acid is also known as ____ 

• Desenex

• Cruex

[Topical Antifungal Agents]
Undecylenic acid BRAND NAMES are ___ [2]

Undecylenic acid

[Topical Antifungal Agents]
____- is obtained from the destructive distillation of castor oil (ricinoleic acid). 

castor oil

[Topical Antifungal Agents]

ricinoleic acid is also known as  ____-

Castor oil

[Topical Antifungal Agents]
____- 

• From Tangan tangan,

• Used as laxative

Triacetin

[Topical Antifungal Agents]
Glyceryl triacetate is also known as ____ 

• Enzactin

• Fungacetin

[Topical Antifungal Agents]
Triacetin BRAND NAMES are ___ [2]

Salicylic acid

[Topical Antifungal Agents]
____- is a white crystalline powder that is used as an antifungal and keratolytic agent.

Resorcinol

[Topical Antifungal Agents]

m-hydroxyphenol is also known as ____ ?

Resorcinol 

[Topical Antifungal Agents]

____- is a white crystalline powder that is used as an antiseptic and keratolytic agent.

Benzoic acid

[Topical Antifungal Agents]
_____- is the only anti-fungal that cannot penetrate the skin

Whitfield's ointment

[Topical Antifungal Agents]

Salicylic acid + Benzoic acid with ratio 1:1

True

[Topical Antifungal Agents]
[TRUE or FALSE] 

White petrolatum is used as base

Phenol and their derivatives

[Topical Antifungal Agents]
____ - interfere with cell membrane integrity and function in susceptible fungi

Halotex

[Topical Antifungal Agents]
Haloprogin BRAND NAME is _____

Haloprogin

[Topical Antifungal Agents]
___- is a treatment of superficial tinea infection

Vioform®

[Topical Antifungal Agents]

Clioquinol  BRAND NAME  is  ____ 

Clioquinol

[Topical Antifungal Agents]
____-

• Is use as a substitute for iodoform

• Treatment of jock itch and athlete's foot

3%

[Topical Antifungal Agents]
Clioquinol  ____ % is a treatment for vaginitis

Clioquinol   3%

[Topical Antifungal Agents]
____- is a treatment for vaginitis

Loprox®

[Topical Antifungal Agents]

Ciclopirox olamine  BRAND NAME  is _____ 

Ciclopirox olamine

[Topical Antifungal Agents]
____ is a broad spectrum topical anti-fungal

Ciclopirox olamine

[Topical Antifungal Agents]
____- is the Agent of choice (AOC) for cutaneous candidiasis, tinea corporis, tinea crusis, tinea pedis, tinea versicolor

Ciclopirox olamine

[Topical Antifungal Agents]

____- is  the second line agent for onychomycosis (infection of nailbeds)

Onychomycosis

___- is the infection of nailbeds 

Flucytosine

[Nucleoside Antifungal Agent] 
5-FC is also known as ___

Ancobon®

[Nucleoside Antifungal Agent] 
 Flucytosine BRAND NAME is ___

Flucytosine

[Nucleoside Antifungal Agent] 

____-

• The only nucleoside antifungal agent

• orally active narrow spectrum agent

Flucytosine

[Nucleoside Antifungal Agent] 
____- is a treatment of Candida and Cryptococcus species infections

Polyenes:

1) Amphotericin B

2) Nystatin

3) Natamycin

Others:

1) Griseofulvin

Anti-fungal Antibiotics

Polyenes

_____- are isolated from soil bacterium streptomyces and the structural requirements

bacterium streptomyces

Polyenes   are isolated from soil ______ and the structural requirements

Polyenes

____- acts as false membrane, bind to ergosterol to inhibit it

1. Large lactone ring (26C for Natamaycin, 38C for Amphotericin B and Nystatin)

2. Series of OH groups on the acid portion of the ring

3. Glycosidically linked deoxyaminohexose sugar: MYCOSAMINE conjugated double bonds:

1) Natamycin - pentaene

2) Nystatin - hexaene

3) Amphotericin B - Heptaene

Structural requirements of polyenes

Mycosamine

Deoxyaminohexose sugar of polyenes

1) Natamycin

2) Nystatin

3) Amphotericin B

Conjugated bonds of Polyenes

1) pentaene

2) hexaene

3) heptaene

Amphotericin B

Fungizone

isolated in 1956 by Gold et. al from Streptomyces nodosus

amphoteric substance

used to treat serious potentially life threatening infections

parenteral form (except IM) is an aqueous colloidal dispersion stabilized by sodium deoxycholate

last line agent for systemic fungal infections because it is nephrotoxic; 80-85% of patient will develop nephrotoxicity

sodium deoxycholate

used to stabilize parenteral Amphotericin B

1. Amphocil and Amphocyte

2. Abelcet

3. AmBisome

Forms of Amphotericin B: (Amphocil and Amphocyte, Abelcet, AmBisome)

1. Colloidal dispersion

2. (7:3 molar) phospholipid mixtures

3. Liposomal form

Nystatin

Mycostatin

Isolated by Hanzen and Brown (1951)

ring aglycone is nystatinolide

Natamycin

Natacyn

from Streptomyces natalensis

treatment of conjunctivitis, blepharitis, and keratitis

Griseofulvin

Grisovin

first reported by Oxford et. al and isolated from Penicillium griseofulvum

very lipophilic

static action

MOA: mitotic spindle poison - binds with the tubulin dimes required for microtubule assembly

Allylamines and related compounds

True allylamines:

1. Naftifine HCl

2. Terbinafine

Similar action:

1. Tolnaftate

Allylamines

MOA: squalene epoxidase inhibitor

Naftifine HCl

Naftin

1% cream gel used topically against ringworm, athlete's foot and jock itch

Terbinafine

Lamisil

use is same with naftifine but active against onychomycosis

more effective than naftifine when it comes to spectrum of action

Tolnaftate

Tinactin

thioester of B-naphthol that inhibits squalene epoxidase having cidal action

Azole Antifungals

MOA: Lanosterol 14 alpha demethylase inhibitor

synthetic antifungal agents with broad spectrum of activity and unique mechanism of action

Miconazole Nitrate

Daktarin

treatment for systemic fungal infection and chronic mucocutaneous candidiasis

Ketoconazole

Nizoral

1st orally active broad spectrum imidazole

useful for systemic infection

hepatotoxic, can lead to gynecomastia

highly protein bound

Itraconazole

Sporanox

biazole: contains 2 triazole moieties which are weakly basic 1,2,4 triazole, and non-basic 1,2,4-triazol-3-one

orally active and broad spectrum

requires acidic environment for optimum absorption

important alternative to ketoconazole

Fluconazole

Diflucan

the only water soluble azole (bis-triazole) with broad spectrum of activity

Agent of choice: cryptococcal meningitis

DOC: fungal meningitis

lead to synthesis of ignosterol which is toxic

Echinocanadins

large cyclic peptides linked to along fatty acid

inhibits the synthesis of 1,3-B-d-glucan synthase resulting to the disruption of the fungal cell wall and cell death

Echinocanadins products (fungins)

Caspofungin

Micafungin

Anidulafungin

Aureobasidins

cyclic depsipeptide produced by Aureobasidium pullulan

MOA: acts as a tight binding noncompetitive inhibitor of the enzyme inositol phosphoryl ceramide (IPC) synthase

IPC synthase

essential for fungal sphingolipid biosynthesis

1. Undecylenic acid

2. Amphotericin B

3. Nystatin

4. Natamycin

5. Griseofulvin

Antifungal Agents Sources:

1. destructive distillation of castor oil

2. Streptomyces nodosus

3. Streptomyces noursei

4. Streptomyces natalensis

5. Penicillium griseofulvum

1. Phenol and their derivatives

2. Polyenes

3. Griseofulvin

4. Allylamines

5. Azoles

6. Echinoacanidins

7. Auerobasidins

Antifungal Agents MOA:

1. interfere with cell membrane integrity and function in susceptible fungi

2. act as false membrane; bind and inhibits ergosterol

3. mitotic spindle poison: bind with the tubulin dimes required for microtubule assembly

4. squalene epoxidase inhibitor

5. lanosterol 14 alpha demethylase inhibitor

6. inhibits 1,3-B-d-glucan synthase resulting to disruption of fungal cell wall and cell death

7. tight binding noncompetitive inhibitor of the enzyme Inositol Phosphorylase Ceramide Synthase

1. Ciclopirox olamine

2. Clioquinol

3. Flucytosine

4. Amphotericin B

5. Terbinafine HCl

6. Ketoconazole

7. Itraconazole

8. Fluconazole

9. Miconazole nitrate

Antifungal Agents Distinct Uses:

1. Agent of choice for cutaneous candidiasis, Tinea corporis, Tinea pedis, Tinea cruris, Tinea pedis, Tinea versicolor

1. Second line agent for onychomycosis (infection in nail beds)

2. Substitute for iodoform

3. Treatment of systemic Candida and Cryptococcus spp. infections

4. for potentially life threatening infections; last line agent for systemic fungal infections

5. use is same as naftifine (ringworm, athelete's foot, jock itch) but active against onychomycosis

6. 1st orally active broad spectrum imidazole

7. alternative to ketoconazole

8. AOC for cryptococcal meningitis; DOC for fungal meningitis

9. treatment for systemic fungal infection and chronic mucocutaneous candidiasis