Inhibition of squalene epoxidase and sterol side-chain methylation by allylamines.

Irrtrotliictiori The allylamines arc a recently developed class o f synthetic antifungal agents 1 1 1 with clinical applications against pathogenic fungi. The topical antimycotic na temically active compound terbinafine inhibit a wide range of fungi. with a strictly fungicidal action in most cases [2, 31. A large number of structurally related allylamines have been synthesized; the chemistry and structure-activity rclationships of these compounds have recently been reviewed by Stuetz 141. All the currently available evidence (reviewed in 151) indicates that the antifungal activity of naftifine and terbinafine is due entirely t o inhibition of fungal ergosterol biosynthesis. The same mode of action has been found in a considerable number of other allylamines which have been investigated. The primary action of these drugs is the inhibition of fungal squalene epoxidase (squalene mono-oxygenase; EC 1.14.99.7) [6] and indeed naftifine was the first specific inhibitor of this enzyme to be identified. Squalene epoxidase plays an essential role in the conversion of the hydrocarbon squalcnc to the rigid sterol ring structure which is required for membrane function in nearly all fungi. The enzymology of squalene epoxidase and its inhibitors has been rcccntly reviewed 171. At high concentrations, naftifine can also inhibit some other biochemical processes including the sterol side-chain C-24 methylation in C'undirlu ulhicurzs 1x1.