1: Antimicrob Agents Chemother  2001 Dec;45(12):3347-54

Experimental and conformational analyses of interactions between butenafine and

Mingeot-Leclercq MP, Gallet X, Flore C, Van Bambeke F, Peuvot J, Brasseur R.

Unite de Pharmacologie Cellulaire et Moleculaire, Universite Catholique de
Louvain, B-1200 Brussels, Belgium.

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.

PMID: 11709307 [PubMed - in process]