Download Antifungal Agents

Antifungal Agents
Most of the fungal infections are superficial invasion of skin or
mucosal membrane of the body orifices. It can be controlled by
local application of antifungal agent.
Antifungal infections are divided into two groups
1. Dermatophytoces- (tinea infection) it is a superficial skin
infection caused by Epidermophytons, Microsporum and
Trichophyton species.
2. Mycoces- it is contagious usually superficial infection
involving skin and mucous membrane caused by pathogenic
yeast, under certain condition it invade deeper body cavities
causing systemic mycoces.
• Fatty acids are found to be fungistaic in action so copper and
zinc salt are used.
• Aromatic acids- salicylic acid – keratolytic activity
• Certain alkylated and halogenated phenols are also found to
be topical fungistatic in action.
• Imidazole possess highly antifungal activity analogues to 1,2,4
triazole.
• Allylamines – Nafitifine, Terbinafine are also used in local
infections.
• Azoles – early members of azole were highly substituted with
imidazole ring. Later isosteric replacement of imidazole
with1,2,4 triazole ring retained the activity. Hence general
term azole is applied to antifungal agents.
Classification
• Polyene Antibioics
Amphoterecin B, Nystatin, Griseofulvin
• Azoles
Imidazole- Clotrimazole, Ketokonazole, Miconazole
Triazoles- Fluconazole and Itraconazole
• Allylamines- Naftifine, Butenafine, Terbinafin
• thiocarbamate- Tolnaftate
• Antimetabolite- Flucytocin
Polyene Antibiotics
• Before 1950’s undecyclenic acid i.e. mixture of benzoic
acid and salycyclic acis was used.
• Polyene antibiotics are used against deep seated
infections.
• Polyene are macrocyclic lactone with distinct
hydrophilic and lipophilic region. Hydrophilic region
constitute of several alcohol, carboxylic acid and sugar
while lipophilic region constitute of chromophore of
four to seven conjugate double bonds.
• Number of conjugate bond is directly proportional to
antifungal activity. Amphotericin B is 10 fold fungitoxic
with 7 conjugate double bond.
Mechanism of action polyene antibiotics
• The polyene have an affinity for the ergosterol,
insert into membrane, disrupt the function.
• The lipophilic polyene portion cross the lipid
bilayer forming pore in cell membrane.
• As a result the cell membrane become leaky and
cell die due to loss of essential amino acids, ions
and small organic molecule.
• Polyene have great affinity for the ergosterol
containing cell membrane than the cholesterol
containing cell membrane.
Amphotericin B
O H
O H
H 3C
O
O H
H O
O
C H
O H
O H
O H
O H
O
C O O H
3
H 3C
O
C H 3
O H
O
N H
2
O H
3 3 - ( 4 -A m in o - 3 ,5 -d ih y d r o x y - 6 -m e th y l- te tr a h y d ro - p y ra n -2 - y lo x y ) -1 ,3 ,5 ,6 ,9 ,1 1 ,1 7 ,3 7 - o c ta h y d r o x y - 1 5 ,1 6 ,1 8 - trim e th y l- 1 3 -o x o - 1 4 ,3 9 d io x a - b ic y c lo [3 3 .3 .1 ]n o n a tria c o n ta - 1 9 ,2 1 ,2 3 ,2 5 ,2 7 ,2 9 ,3 1 -h e p ta e n e - 3 6 -c a r b o x y lic a c id
A M P H O T E R IC IN B
• Amphotericin B low toxicity to mammalian cells so can be administered IV.
• A/E- fever, shaking chills, hypotension and kidney toxicity.
• It’s a safe drug for systemic infection as it does not cross BBB
• Nephrotoxicity is a serious drawback of this as it is sparingly soluble
in water. It is formulated as a complex with deoxycholic acid for it IV
administration.
• Recently liposomal encapsulation and lipid soluble complex is
formed which reduced this A/E.
Nystatin
OH
OH
H 3C
O
HO
OH
O
OH
OH
OH
OH
O
CH 3
COOH
H 3C
O
CH 3
OH
O
NH 2
OH
33-(4-Amino-3,5-dihydroxy-6-methyl-tetrahydro-pyran-2-yloxy)-1,3,4,7,9,11,17,37-octahydroxy-15,16,18-trimethyl-13-oxo14,39-dioxa-bicyclo[33.3.1]nonatriaconta-19,21,25,27,29,31-hexaene-36-carboxylic acid
NYSTATIN
• It is isolated from culture of streptomyces noursei.
• It is effective against the topical fungal infection. It is available in
cream and ointment.
It is too toxic to use systematically but due to low oral bioavailability it
is used in the treatment of oral and GIT fungal infection.
Griseofulvin
OCH3
4
3
2'
5
3'
1'
6
H3CO
OCH3
O
4'
2
O1
7
Cl
6'
O
5'
H3C
GRISEOFULVIN
• 7-chloro-2’,4,6- trimethoxy-6’-methyl-spiro[benzofuran-2(3H)-1’[2]cyclohexene]-3,4’dione.
• It is antibiotic obtained from fungus penicillium griseofulvum.
• It is a natural spiro compound.
• It is used to treat systemic ringworm infection of body, hair, nails,
feet caused by trichophyton, microsporum, epidermophyton.
• A/E are allergic reactions like rash, articaria, headache,
dizziness, insomnia.
• Oral bioavailability is very poor as it is lipophilic drug.
Bioavailability is increased by micronized form of drug.
• Patient is advice to take griseofulvin with fatty meal.
MOAGriseofulvin is mitotic spindle poison. It cause rapid reversible
dissolution of mitotic spindle apparatus probably binding to the
tubulin dimer that is required for microtubule assembly. Its high
conc. Found in tissue rich in keratin, to treat dermatophytes
infection.
Ergosterol biosynthesis inhibitor.
• Non steroidal precursor to both ergosterol and cholesterol is
squalene.
• It is converted to squalene epoxide by enzyme squalene epoxidase
which is cyclized to lanosterol.
• Key step in conversion of lanosterol to both ergosterol and
cholesterol is removal of 14α methyl group. This step is carried out
by CYP 450 enzyme 14α demethylase.
• The mechanism is three successive hydroxylation converting
hydrocarbon into the alcohol, then aldehyde and carboxylic acid
oxidation.
• Methyl group is eliminated as formic acid and double bond is
formed between C14 and C15 of ring D.
Mechanism of action azoles
• All the azoles act by inhibiting ergosterol biosynthesis through
inhibition of 14α demethylase enzyme.
• Basic N3 of azole form bond with heme iron of CPY 450 in position
normally occupied by activated oxygen.
• This cause inhibition of demethylase result in accumulation of
fungal cell membrane of sterol that still bear 14 methyl group which
does not have shape and physical properties of normal cell
membrane sterol.
• This result in permeability change, leaky membrane and
malfunction of embedded proteins.
• This leads to fungal cell death.
• The relative strength of same enzyme differ in different species
hence mammalian enzyme is not affected.
Clotrimazole
N
N
C l
1 -[(2 -C h lo ro -p h e n y l)-d ip h e n y l-m e th y l]-1 H -im id a z o le
C L O T R IM A Z O L E
• It is broad spectrum antifungal agent used to treat tinea infection
and candidiasis.
• It is active against many pathogenic yeast it cause severe GIT
disturbance.
Miconazole
Cl
Cl
Cl
O
Cl
N
N
1-[(2,4-Dichloro-phenoxy)-(2,4-dichloro-phenyl)-methyl]-1Himidazole
MICONAZOLE
• It is available in free base form for injection, solubalized in PEG and
castor oil.
Ketoconazole
O
N
CH3
N
Cl
Cl
O
O
O
N
N
1 -(4 -{4 -[2 -(2 ,4 -D ich lo ro -p h en y l)-2 -im id azo l-1 -y lm eth y l-[1 ,3 ]d io x o lan -4 -y lm eth o x y ]-p h en y l}-p ip erazin -1 y l)-eth an o n e
KETOCONAZOLE
•It is widely used to treat systemic infection. It need low stomach PH
for its absorption.
•Antacid or drug that rise that PH of stomach will lower the conc of
ketokonazole.
•CYP 3A4 play significanr role I metabolism of ketoconazole (CYP3A4
inducer drug like phenitoin, carbamezepin and rifampin ) reduce the
conc by 50%.
•Ketokonazole is inhibitor of CYP3A4 cause increase in conc of
triazolam.
•Ketoconazole is weak inhibitor of CYP2C9 cause metabolism of
warfarin and phenytoin.
O
NH
N
N
Cl
N
CH3
Cl
Cl
O
O
Cl
O
O
O
DEACETYLASE
O
N
N
N
N
O
O
NH
N
NH2
H
N
Cl
Cl
O
O
Cl
Cl
O
O
O
N
O
N
N
N
NH2
Cl
Cl
O
O
O
N
N
METABOLISM OF KETOCONAZOLE
Itraconazole
CH3
N
N
N
C 2H 5
O
N
N
Cl
Cl
O
O
O
N
N
N
2-sec-Butyl-4-[4-(4-{4-[2-(2,4-dichloro-phenyl)-2-[1,2,4]triazol-1-ylmethyl-[1,3]dioxolan-4-ylmethoxy]-phenyl}-piperazin-1-yl)-phenyl]2,4-dihydro-[1,2,4]triazol-3-one
ITRACONAZOLE
• Itraconazole along with fluconazole is first triazole introduced into
clinical use.
• It require strongly acidic PH for its absorption.
• Like ketoconazole it is extensively metabolised by CYP3A4.
• Its oral bioavailability is greatly reduce by co administration of
CYP3A4 inducer Phenytoin, carbamazepin, rifampin
• This has significance because risk of development of rhabdomylosis
followed by co administration of lovastatin and simvastatin
Fluconazole
F
F
OH
N
N
N
N
N
N
2-(2,4-Difluoro-phenyl)-1,3-bis-[1,2,4]triazol-1-yl-propan-2-ol
FLUCONAZOLE
• Fluconazole is introduced at the same time that if itraconazole and
ketoconazole.
• It is equally bioavailable when given orally or IV.
• It has two advantages over other antifungal agents that it can cross
BBB and it is weak inhibitor of CYP 3A4.
• It is strong inhibitor of CYP 2C9 by which it increase the conc of
warfarin to extreamly harmful level.
Structure activity relationship
• The basic structural requirement is weak basic imidazole ring or
1,2,4-triazole ring bonded by N-C linkage to rest structure.
• At molecular level N3 of imidazole and N4 of triazole bind to the
heme iron of enzyme CYP450 to inhibit activation of molecular
oxygen.
• Most potent azole possess 2 or 3 aromatic ring at least one of which
is halogen substituted.
• Nonpolar functional group at 2 or 2,4 yield effective azole
compound.
• The halogen atom that yield most potent compound is fluorine.
• Sulfonic acid substitution yield potent drug.
• Substitution at other position leads to inactive compound.
• nonpolar functionality increase lipophilicity.
Allylamines
• The group of agents generally known as
allylamines strictly include nafitifine and
terbianfine.
• The benzyl group of butenafine to be bioisosteric
with allyl group of nafitifin and terbinafine.
• Tolnaftate a much older drug chemically it is
thiocarbamatebut has same mechanism of action
of allylamines.
• It has limited spectrum of activity than azole,
therefor employed in the treatment of skin and
nail fungal infection.
MOA
• All the drug act by inhibition of squalene
epoxidase.
• It result in decrease in total fungal sterol content
of cell membrane.
• It change the physicochemical properties of
membrane.
• It cause malfunction of membrane embedded
protein involved in nutrient transport and PH
balance.
• Secondly it result in formation of cell wall with
squalene, which itself is toxic when present in
high amount.
Nafitifin
CH3
N
M
ethyl-naphthalen-1-ylmethyl-(3-phenyl-allyl)-amine
NAFITIFINE
•First allylamines discovered and marketed subject to first pass
metabolism to orally active. It is bioavailable only in topical
preparation. Used in tinea infection.
Butenafine
C
H
3
N
B
U
T
E
N
A
F
IN
E
[3
-(4
-tert-B
u
ty
l-p
h
en
y
l)-ally
l]-m
eth
y
l-n
ap
h
th
alen
-1
-y
lm
eth
y
l-am
in
e
• Used in treatment of topical dermatophyte infection.
• It has wide spectrum of activity than tolnaftate.
• Butenafine is effective against superficial C. albicans infection which
is not treated by tolnaftate.
Terbinafin
CH3
N
(6,6-Dimethyl-hept-2-en-4-ynyl)-methyl-naphthalen-1-ylmethyl-amine
TERBINAFINE
• it is available in oral and topical form. Used in the treatment of
onychomycoses i.e. nail infection.
• It is given orally, redistribute from plasma to nail bed.
Tolnaftate
C
H
3
O
S
N
C
H
3
M
e
t
h
y
l
m
t
o
l
y
l
t
h
i
o
c
a
r
b
a
m
i
c
a
c
i
d
O
n
a
p
h
t
h
a
l
e
n
2
y
l
e
s
t
e
r
T
O
L
N
A
F
T
A
T
E
• Tolnaftate is a thioester of β-naphthol is fungicidal against
dermatophytes that cause tinea infection.
• It is available in 1% cream, powder, gel, solution to treat ringworm
infection.
• It is inhibitor of squalene epoxidases so it is classified under
allylamines.
• It is formulated into artificial fingernails to counteract the ringworm
infection of nail bed.
Flucytosine
NH2
O
F
F
N
O
HN
N
H
Fungal cytosine
deaminase
5-FdUMP
O
N
H
4-Amino-5-fluoro-1H-pyrimidin-2-one
FLUCYTOSINE
• it is a powerful antifungal used in the treatment of systemic fungal
infection as cryptococcus neoformus, candidia sp.
• It is cytotoxic, is a prodrug which is metabolized to 5FU, which is
converted to 5-fluorodeoxyuridine.
• 5-fluorodeoxyuridine is thymidylate synthase inhibitor that interfere
both protein and RNA synthesis.
• Resistance rapidly develops so it is given in combination of
amphotericin B.
• Now fluconazole is used in place of flucytosine.