Butenafine (N-4-tert-butylbenzyl-N-methyl-1-naphtalenemethylamine hydrochloride) is an
antifungal agent of the
benzylamine class that has excellent therapeutic efficacy and a remarkably long duration of action when applied topically to treat various
mycoses. Given the lipophilic nature of the molecule, efficacy may be related to an interaction with cell membrane
phospholipids and permeabilization of the fungal cell wall. Similarly, high lipophilicity could account for the long duration of action, since fixation to
lipids in cutaneous tissues might allow them to act as local depots for slow release of the
drug. We have therefore used computer-assisted conformational analysis to investigate the interaction of
butenafine with
lipids and extended these observations with experimental studies in vitro using
liposomes. Conformational analysis of mixed monolayers of
phospholipids with the neutral and protonated forms of
butenafine highlighted a possible interaction with both the hydrophilic and hydrophobic domains of membrane
phospholipids. Studies using
liposomes demonstrated that
butenafine increases membrane fluidity [assessed by fluorescence polarization of 1-(4-trimethylammonium-phenyl)-6-phenyl-1,3,5-hexatriene and
1,6-diphenylhexatriene] and membrane permeability (studied by release of
calcein from
liposomes). The results show, therefore, that
butenafine readily interacts with
lipids and is incorporated into membrane
phospholipids. These findings may help explain the excellent antifungal efficacy and long duration of action of this
drug when it is used as a topical
antifungal agent in humans.