SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF SIDE-CHAIN-SUBSTITUTED ANALOGS OF THE ALLYLAMINE ANTIMYCOTIC TERBINAFINE LACKING THE CENTRAL AMINO FUNCTION

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.