Overview of Microorganism

ANTIFUNGAL AGENTS

Beta glycan and

Chitin

Ergosterol

• Lipid bilayers required sterols as stiffening agent

to hold their shape and their functions.
Mycosis: A disease caused by infection with a fungus, such as ringworm or
thrush.
 There are several fungal species which are pathogenic for human beings.
 Fungi causing infections of hair, mucous membranes, nails or skin include
Candida,
Epidermiphyton, Microsporum etc.

Types of fungal infections (Mycosis)

Superficial
• Affect skin or mucous membrane
• Dermatophytes: Fungi that affect keratin layer of skin, hair, nail. (keratinized
layer of skin)
• Candidiasis: Oral thrush, vaginitis.

Systemic infections
• Affect internal organs as: lung, heart, brain.
1.Superficial mycosis: Most common fungal infections of the skin, hair, and nail that invade only the
stratum corneum and the superficial layers of the skin. (Fungi and Dermatophytes including various forms of tinea, or
ringworm).
The causative microbes are specialized saprophytes, have ability to digest keratin.

a. Cutaneous infections (Dermatophytoses)

 Superficial infections of the keratinized epidermis and keratinized epidermal appendages (hair and nail)
 It cause by Tinea or Ringworm (Trichophyton)
 Trichophyton rubrum (nails, beard, smooth skin)
 Trichophyton tonsurans (scalp, beard, nails)
 Trichophyton violaceum (scalp, skin nails)
 Trichophyton mentagrophytes (athlete’s foot)
Trichophyton is commonly found on floors and in clothing
b. Subcutaneous fungal infections
 Fungal infections in both the skin and subcutaneous tissue, not in internal organs
 Diseses: Chromomycosis, sporotrichosis, mycetoma, lobomycosis
 Chromomycosis: is a chronic fungal infection of the skin and subcutaneous tissue caused by any of several pigmented fungi normally
found in soil and wood

2. Systemic Mycoses

 Deep seated, systemic mycoses have sporadic distribution, fungal spores live in soil and act as primary pathogen
 Disease caused by the systemic organisms (Histoplasmosis, sporotrichosis, blastomycosis, cryptococcosis)
 Fungal spores are inhaled into the lung, and enter into systemic circulation
 Histoplasmosis: Histoplasma capsulatum
 Blastomycosis: Blastomyces dermatidis
 Cryptococcosis: Cryptococcu neoformans
 Spototrichosis: Sporothrix schenckii
 Coccidioidomycosis: Coccidioides immitis
 Paracoccidioidomycosis: Paracoccidioides brasiliensis
 Opportunistic fungal infections
 Opportunists can grow in nearly every circumstance in which a patients immune system is compromised.
 Require Impairment of host immunity to cause serious disease
 Recent years, bcz of overuse of antibacterial antibiotics, steroids and immunosuppressive agents a new systemic
mycoses become prominent.
 Yeast : Candida (systemic candidiasis)
Cryptococcus
 Fungi: Aspergillus (Aspergillosis)
 Ex: Oral candidiasis is most common in poorly nourished persons,
in patients on immunosppressive dugs,
and in persons with AIDS.
 Pneumocystis carinii is an organism responsible for life threatening pneumonia
Antifungal Agents
 Antifungal agents

Antibiotics Synthetic Drugs Topical Agents

• Polyene antibiotics • Imidazoles
Fatty acids: Propionic acid
Econazole, Oxiconazole Zinc propionate
Amphotericin B
Ketoconazole, Tionazole Undecylenic acid
Nystatin Clotrimazole, Butoconazole Sodium Caprylate
Hamycin Miconazole Salicylic acid and Resorcinol
• Griseofulvin • Triazoles Benzoic acid
Terconazole, Fluconazole, Itraconazole
• Pyrimidine analogues
Flucytosine
Allylamine
Terbinafine, Naftifine
•Substituted pyridine
Cyclopirox
•Morpholine
Amorolfine
Miscellaneous compounds
Tolnaftate , Undecylenic acid
 CLASSIFICATION OF ANTIFUNGAL AGENTS
1. Cell wall Inhibitor
Griseofulvin
Caspofungin
2. Cell Membrane Inhibitors (Inhibit ergosterol synthesis)
a. Imidazoles: Econazole, Oxiconazole
Ketoconazole, Tionazole
EKCMBOT
Clotrimazole
Miconazole
Butoconazole
b. Triazoles: Terconazole,
FIT Fluconazole,
Itraconazole,
Voriconazole
c. Allylamines: Naftifine
Tolnaftate
d. Morpholines: Amorolfine

e. Substituted pyridines: Ciclopirox

3. Nucleic acid Inhibitors
5-flucytosine
(Allylamines)
(Imidazole, Triazole)
 Antifungal Antibiotics:

Griseofulvin:
Spiro compound
Methoxy

Dione

Cyclohexene
Benzofuran
Uses: Ringworm infections of the body, hair, nails, and feet
MOA: Fungistatic agent, Prevents reinfection and promote development of new healthy tissue
Continue until all infected tissue exfoliated

Adverse effect: Allergic reactions (Rash, urticarial)

GI upset,
Headache, dizziness, insomnia
 Polyene antibiotics

Chemistry :
• Polyene chain is a part of macrocyclic lactone ring (system of conjugated double bonds-ene)
• An amino-sugar (usually mucosamine) is glycosidically linked to the macrolide aglycone)

Aglycone

16

19
Polyene chain
Mucosamine

Amphotericin B
• 38 membered macrocyclic ring.
• Has seven double bonds in trans disposition
• Mucosamine is glycosidically linked through position 19 of macrolide aglycone
• Presence of primary – COOH gp. At 16 position.
Source of Amphotericin

 Isolated from Streptomyces nodsus

 Gives mix of amphotericin A,B

 Amphotericin B is more active

 Amphoteric in nature

 Polyene act as ‘false membrane components’,

Mechanism of action
ergosterol ergosterol with
pore

+ a polyene

• It binds selectively to sterols, chiefly ergosterol present in the membranes of

sensitive fungi
• So it forms pores or channels  results in increase in the permeability of the
membrane  leakage of variety small molecules
• Antifungal drugs must have a higher affinity for ergosterol versus chloesterol to
explain their toxicity to the fungal cell
• Fungistatic at low concentrations and Fungicidal at high concentration
Solubility
• Amphoteric substance
•Deep yellow crystals
•Sparingly soluble in organic solvents but insoluble in water

Spectrum
 Active against Candida species
Cryptococcus neoformans
Histoplasma capsulatum
Coccidiodes immitis
Paracoccidiodes brazilensis
Aspergillus spp.
• A Limited activity against Leishmania protozoa also
• No antibacterial activity
Indications
• By IV infusion : Life threatening fungal infections
• Amphotericin B as colloidal complex with sodium deoxycholate (micelles)  in the treatment of
serious Mycotic and protozoal infections. (Store in refrigerator and Protect from light)
like histoplasmosis,
coccidiomycosis and
sporotrichosis.
• Orally : For intestinal candidiasis
• Fugal infections in CNS: Cryptococcosis; Amphotericin B mixed with Cerebrospinal fluid (CSF) from spinal tap
Than mixture reinject in spinal tap
Severe infections: Repeat many times
Adverse effect
Nephrotoxicity,
fever,
headache,
anorexia,
GI distress.
2. Nystatin
 Source : Sterptomyces noursei
 Properties : Yellow to light tan powder, Slightly soluble in water, sparingly soluble in organic solvent
 Structure : Related to amphotericin B
Here, 38 membered Macrolide ring has separate tetraene and diene chromophores isolated from each
other by a methylene gp.

• Spectrum : Mainly candidia spp

Uses
• Its main action is against candidiasis of skin and mucus membranes.
• It is toxic therefore not used systemically.
• Not used systemically
• Not absorbable by oral route so Applied topically
• Toxic – and therefore not used systemically but used in treatment of candidiasis of skin and mucous
membrane (local action)
• MOA : Similar to Amphotericin
3. Natamycin
Source : Streptomyces natalensis
Structure
 26 membered lactone ring containing tetraene, carbonyl group, three hydroxyl, epoxide and Mucosamine.
 Amphoteric in nature
Mechanism of Action
 Fungistatic and cell lysis at low concentration, Fungicidal at high
Epoxy
 Potassium ion leakage and cell lysis Carbonyl

Uses
Conjunctivitis and keratitis.

Tetraene

Mucosamine
 Synthetic antifungal agents:

AZOLE
Mechanism of Action of AZOLEs:
Azoles inhibit ergosterol synthesis

Allylamine drugs inhibit synthesis of Ergosterol and Lanosterol

• Inhibition of fungal sterol- 14-α-demethylase,

a cytochrome P450-dependent enzyme

• Results in blockade of ergosterol synthesis

Alteration in the permeability of cell membrane
of fungi

• Higher concentration of them are required to

inhibit cholesterol synthesis in mammalian
cells, so selective antifungals.
SAR OF AZOLEs:
Azole class is a weekly basic 1, 3 imidazole or 1,2,4 triazole ring bonded by N-C linkage to rest structure; Important for activity
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 oxidation.

Substitution
 Must be on N 1 position, other position will lose the activity
Most
 potent antifungal azole- two or three aromatic rings, at least one of which is halogen substituted E.G. 2,4-dichlorophenyl (Miconazole),
4- Chlorophenyl (Econazole),
2,4 difluorophenyl
Only 2 and/or 2,4 substitution yield effective azole compounds


3
1

4 1

2


4
The
 halogen atom that yields the most potent compounds is fluorine, although functional groups as sulfonic acids

The
 free bases are insoluble in water, but soluble in most organic solvents as ethanol
Exception: Fluconazole
 it is sufficiently water soluble to be injected intravenously as solution of free base.

Fluconazole


Clotrimazole:
Imidazole

O-chloro

Spectrum : Broad
Weak base, white crystalline solid, sparingly soluble in water but soluble in alcohol and organic
Mechanism of Action
 Write MOA of azole
Uses
 Topically for tinea infections and candidiasis (bcz Severe GI disturbances)
Econazole and Miconazole:
Structure
N Imidazole
Methoxy
N

CH2 O CH2
CH
X Cl

Cl Miconazole  X = Cl
Cl
Econazole  X = H
Chlorophenyl
 Indications

Applied topically as creams, lotions &

}
Econazole nitrate powder in the treatment of –
Clotrimazole - Candidiasis of skin
- tinea
Creams & pessaries
- Vaginal candidiasis

Miconazole  Orally  for oral & intestinal candidiasis

 IV or infrathecal  for severe systemic fungal infections of candidiasis,
Coccidiomycosis, Cryptococcosis, Paracoccidiomycosis
 Butoconazole: Oxiconazole:
 2% cream for treatment of vaginal candidiasis
Imidazole

Butane
Ketoconazole
Broad spectrum antifungal agents

Dioxolan

Methoxy

Piperazine

• Ketoconazole is racemic mixture of two of two enantiomers,

Levo ketoconazole ((2S,4R)-(−)-ketoconazole) and
Dextro ketoconazole ((2R,4S)-(+)-ketoconazole).
Indications
Orally  used in the treatment of systemic fungal infections
- Tinea infections of skin & finger nails
Topical applications cream /Shampoo
- 2% concentration in cream and in shampoo for cutaneous candidiasis and tinea infections
Systemic adminstration 
- Treatment of non meningeal blastomycosis,
candidiasis
histoplasmosis

The antifungal actions of Ketoconazole and Polyene antibiotic Amphotericin B are

reported to antagonize each other.
 N
Fluconazole N
N
CH2
N
N CH2 OH
N
F

F
Two triazole ring
Orally  for treatment of deep organ Candidiasis
IV  Cryprococcai meningitis
Terconazole
triazole

Piperazine
Methoxy

Dioxolan
Itraconazole (Unique, Two triazole moieties)
Triazole
Methoxy

Dioxolan
Piperazine
Triazole 3-one
Allylamines:
Naftifine hydrochloride, Tolnaftate
Allylamines:
Naftifine hydrochloride

Methanamine
For Tinea infections

Napthalene

Tolnaftate
Thioester of Beta napthol
Used to treat ringworm, Athletes foot
Available in Cream, powder, aerosol, gels
Napthalene and solution
Synthesis

1. Tolnaftate
2. Miconazole
TOLNAFTATE

O-naphthalen-2-yl N-methyl-N-(3-methylphenyl)carbamothioate
MICONAZOLE

Sodium tetrahydridoborate

2,4 dichlorophenacylbromide Imidazole

2
1(bromomethyl)-2,4 dichlorobenzene 1

1-[2-(2,4-dichlorophenyl)-2-[(2,4-dichlorophenyl) methoxy] ethyl]

imidazole