Antimycotics
= compounds used for treatment of diseases caused by fungi
(moulds or yeasts)
© Oldřich Farsa 2011
Classification of antimycotics
1. Antimycotic antibiotics
1.1 Griseofulvine
1.2 Polyene antibiotics
1.3 Echinocandins
1.4 Sordarins
2. Flucytosine
3. Azoles
3.1 Imidazole derivatives
3.2 Triazole derivatives
4. Allylamines
5. Morpholines
6. Ciclopirox olamin
7. Unsaturated fatty acids and their salts
8. Esters of glycerole
Sites of action of particular types of antimycotics
1. Antimycotic antibiotics
Griseofulvine
O
O
H
CH3
O
CH3
O
Cl
O
CH3
O
CH3
●
antibiotic isolated from Penicilium griseofulvum in 1939
●
site of action: microtubules formation
●
high toxicity (liver)
●
spectrum: dermatophytes
Griseofulvinum PhEur
Antimycotic antibiotics
Polyene antibiotics
O
OCH3
CH3
OH
CH3
OH
O
OH
OH
OH
OH
OHOHOHO
O O CH3
OH
NH2
OH
H
H
H
H
H
H
amphotericin B
nystatin
Macrolides with larger ring than erythromycine group
Abelcet®
, Amphocil®
●
systemic candidoses and
aspergiloses, sepses caused by fungi
Fungicidin®
ung., Macmiror complex®
ung., sup. (+
furazolidone)
●
efficient to species Aspergillus, Rhodotamba, Torulopsis,
Trichosporon, Candida, Malassezia, Geotrichum etc.
●
in most externally
Antimycotic antibiotics
Polyene antibiotics
O
OH
OH
O
OH
O
OH
O
OH
O
NH2
CH3
OH
O
O
CH3
natamycin
Pimafucin ® , Pimafucort ®
●
external application
Antimycotic antibiotics
Echinocandins

cyclic hexapeptides, OH-Pro dominates in their sequence, a lipophilic side acyl chain

site of action: protein complex responsible for synthesis of β-1,3-glucans of the cell wall
N
NH
CH3
OH
OH
OH
N
H
OH
O
O
N
H
N
H
N
H
N
H
OH
O
O
O
OH NH
NH2
O
O
OH
NH2
H
OH
H
CH3 CH3
CH3
caspofungin
Cancidas plv. inf. sol (acetate)

all usual pathogenic fungi except
Cryptococcus neoformans

approved by FDA for treatment of
aspergilloses in 2001

i.v. administration only
O
CH3
N
O
OH
N
H
O
NH
OH
OH
O
OH
N
H
O
NH2
OH
N
H
OH
O
NH
O
N
O
O
OH
OH
OH
H
CH3
CH3
Antimycotic antibiotics
Echinocandins
anidulafungin
Ecalta ® powder for inf. sol.

invasise candidoses
N
O
OH
N
H
O
NH
OH
OH
O
OH
N
H
O
NH2
OH
N
H
OH
O
NH
O
N
O
O
O
OH
OH
OH
S
O O
O
N
O
O
H
CH3
CH3
CH3
Na
+
Antimycotic antibiotics
Echinocandins
micafungin
Mycamine ® inf. plv. sol.
•invasive candidoses
Antimycotic antibiotics
Echinocandins

preparation of semi-synthetic micafungin (FK 463)
micafungin
•
Natural water-soluble echinocandin
Antimycotic antibiotics
Echinocandins
Intramolecular cleavage of the lactone ring –
lactone aminolysis – in compound FR901469
•replacement of the ester bond with the amide one avoids this peptide ring-opening
Antimycotic antibiotics
Sordarins
OHO
O
O
O
O
O
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
H
GM 193663

metabolite of the mold Sordaria araneosa

first isolated in Sandoz, Switzerland, 1969

mode of action: protheosynthesis inhibition by blocking of fungal elongation factor 2 (EF2) in
translation
(the amino acids sequence of EF2 is in Candida albicans in 85 % equal to this in human)
Spectrum: Candida albicans etc.
OH
H
CH3
CH3
O
H
H HCH3
O
H
O
H
H
H
H
OH
OH
O
CH3
CH3
O
sordarin
2. Flucytosine
N
NO
NH2
F
H
4-amino-5-fluoro-1H-pyrimidin-2-one
5-fluorocytosine
flucytosine
Ancotil®
N
NO
NH2
F
H
N
NO
F
H
O
H
N
NO
F
H
OH
5-fluorouracil
cytosine deaminase

Spectrum: pathogenic yeasts (Candida,
Cryptococcus), strains causing
chromomycoses

Mechanism of action: transformation into 5fluorouracil
by fungal cells ⇒ 5-fluorouracil
inserted into RNA ⇒ inhibition of thymidylate
synthase ⇒ blocking of DNA synthesis
3. Azoles

imidazole (= 1,3-diazole) derivatives

1,2,4-triazole derivatives

the most numerous group of antimycotics
•
mechanism of action: inhibition of 14α-demethylation of lanosterol in biosynthesis of
ergosterol
•
in some species also inhibition of following ∆22 desaturation
⇓

ergosterol is replaced with non-functional sterols ⇒ permeability and fluidity of the cell
membrane is altered ⇒ binding of membrane enzymes including those which are needed
for cell wall synthesis is embarrassed
OH
H
H
H
CH3
CH3 CH3
CH3
CH3 CH3
CH3
CH3
OH
H
H
H
CH3
CH3
CH3
CH3 CH3
CH3
CH3
H
lanosterol 14α − desmethyllanosterol
Azoles
Imidazole derivatives
N
N
Cl
1-[(2-chlorophenyl)diphenylmethyl]imidazole
clotrimazole
Canesten ® , Candibene ® …

mostly external use
Azoles
Imidazole derivatives
Compouns with 1-[2-(phenylmethoxy)-2-phenyl]ethylimidazole fragment

spectrum: dermatophytes, Candida, Malassezia, Geotrichum …

skin and vaginal candidoses

mostly external use
Cl
Cl
O
N
N
Cl
O
Cl
N
+
Cl
N S
HNO3
-
econazole
Gyno-Pevaryl®
supp.
vag.

nitrate
fenticonazole
(fenticonazolium nitrate)
Lomexin®
crm. vag.
Azoles
Imidazole derivatives
S
N
Cl
Cl
N
Cl
N
N
O
Cl
Cl
Cl
Cl
miconazole
Klion-D®
vag. tbl., Loramyc ®
tbl.

spectrum: Candida

vaginal mycoses and mycoses of GIT
butoconazole
Gynazol®

spectrum: dermatophytes,
Candida, Malassezia,
Geotrichum …

skin and vaginal candidoses
Azoles
Imidazole derivatives
ClCl
O
O
N
N H
O
N
N O
ketoconazole
Ketoderm®
crm., Nizoral®
tbl. (not authorised in ČR)

spectrum: dermatophytes, Candida, Malassezia, Geotrichum …

skin, vaginal, GIT candidoses

both external and internal use
Azoles
1,2,4-triazole derivatives
F
F
R
2
OH
R
1
N
N
N
N N
N
N
N
F
S
N
C
N
R1 R2
H
CH3
CH3
fluconazole
Diflucan cps. ..
voriconazole
Vfend tbl.
ravuconazole

systemic mycoses, p.o. application

namely Candida, Cryptococcus
Azoles
1,2,4-triazole derivatives
YO
N
N
N
X X
O
N
N
N
N
N
O
R
2
CH3
R
1
CH3
OH
X Y R1 R2
Cl O H CH3
F CH2
itraconazole
posaconazole

spectrum: Candida, Cryptococcus,
Malassezia, dermatophytes etc.

systemic and visceral mycoses,
tropical mycoses
4. Allylamines

mechanism of action: squalene epoxidase inhibition
N
CH3
CH3
CH3
CH3
terbinafine
Lamisil®

spectrum: dermatophytes, Candida parapsilosis
5. Morpholine derivatives

mechanism of action: inhibition of 2 enzymes in final stage of ergosterole synthesis:
∆14
reductase and ∆8
-∆7
isomerase
N
O
CH3
CH3
CH3
CH3
CH3
CH3
amorolfine
Loceryl®

spectrum: dermatophytes, Candida

topical treatment of superficial mycoses (including those of nails = onychomycoses)
6. Ciclopirox olamine
N
O
O
CH3
NH3
+ OH
Batrafen ®
, Mycoster®

spectrum: dermatophytes, Candida, Malassezia

superficial skin and nail mycoses, candidoses, dermatophytoses
7. Unsaturated fatty acids and their salts
CH2
OH
O
Undecylenic acid
undec-10-enoic acid
Acidum undecylenicum PhEur

traditional constituent of MS (magistralliter = pharmacy-made) antimycotic
preparations

zinc and copper salts also used
Zinci undecylenas PhEur
8. Esters of glycerole
O
O
O
CH3
CH3
CH3
O
O
O
triacetin
propan-1,2,3-triyl triacetate
Triacetinum PhEur