act by inhibiting cytochrome P-450 enzymes, in particular those that are essen-
tial for the biosynthesis of ergosterol, the main steroid found in fungual cell
membranes. This is thought to result in an accumulation of 14a-methylated
sterols, such as lanosterol, in the membrane. These sterols are believed to
increase the membrane’s permeability, which allows essential cellular contents
to leak from the cell, causing ireversible damage and cell death. Azoles also
inhibit P-450 oxidases in mammals but far higher concentrations than those
required to treat fungi are usually required.
SAR studies have shown that a weakly basic imidazole or 1,2,4-triazole rings
substituted only at the N-1 position are essential for activity. The substituent
must be lipophilic in character and usually contains one or more five or
six membered ring systems, some of which may be attached by an ether,
secondary amine or thioether group to the carbon chain. The more potent
compounds have two or three aromatic substituents, which are singly or
multiply chlorinated or fluorinated at positions 2, 4 and 6. These nonpolar
structures give the compounds a high degree of lipophilicity, and hence mem-
brane solubility.
7. 2. 1. 2 Allylamines
Allylamines are synthetic derivatives of 3-aminopropene (Table 7.1) developed
from naftifine, the allylamine group appearing to be essential for activity. They
are believed to act by inhibiting squalene epoxidase, the enzyme for the squalene
epoxidation stage in the biosynthesis of ergosterol in the fungal membrane. This
leads to an increase in squalene concentration in the membrane with subsequent
loss of membrane integrity, which allows loss of cell contents to occur.
Tolnaftate, although it is not an allylamine, appears to act in a similar fashion.
However, allylamines do not appear to significantly inhibit the mammalian
cholesterol biosynthesis.
SqualeneSqualene
epoxidase OO 2 Various stepsErgosterolHO2,3-Oxidosqualene134 SELECTED EXAMPLES OF DRUG ACTION AT SOME COMMON TARGET AREAS