SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF SIDE-CHAIN-SUBSTITUTED ANALOGS OF THE ALLYLAMINE ANTIMYCOTIC TERBINAFINE LACKING THE CENTRAL AMINO FUNCTION
P. Nussbaumer et al., SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF SIDE-CHAIN-SUBSTITUTED ANALOGS OF THE ALLYLAMINE ANTIMYCOTIC TERBINAFINE LACKING THE CENTRAL AMINO FUNCTION, Journal of medicinal chemistry, 38(10), 1995, pp. 1831-1836
Terbinafine is a therapeutically used inhibitor of fungal squalene epo
xidase that has prompted extensive derivatization programs for structu
re-activity relationship studies. In the present study, derivatives of
terbinafine were synthesized that lack the central tertiary amino gro
up but have polar substituents at the tert-butyl residue of the side c
hain. Evaluation of the antifungal potential revealed that representat
ives of this novel structural type can also exhibit broad antifungal a
ctivity, indicating that the central amino function of allylamine anti
mycotics is not essential for inhibition of fungal growth. Potency app
ears to correlate with the polarity of the introduced functional group
s, while broad antifungal activity seems to be restricted to compounds
with basic substituents. The dimethylamino-substituted ''carba-analog
'' of terbinafine (8k) showed the best antimycotic profile within the
whole series.