ALLYLAMINE ANTIMYCOTICS - RECENT TRENDS IN STRUCTURE-ACTIVITY-RELATIONSHIPS AND SYNTHESES

Methods developed for the synthesis of terbinafine-related allylamine antimycotics are reviewed. The synthesis of the en-yne side chains were generally accomplished by means of organometallic reactions. The use of Pd0-catalysed coupling reactions allowed easy access to derivatives bearing sensitive side-chain substituents. As examples, four metabolites of terbinafine were prepared via this procedure. Investigations with the carbon analogue of terbinafine revealed that, within the allylamine antimycotics, the nitrogen appears to be necessary for penetration by the drug into the fungal cell. Replacement of the naphthalene moiety of terbinafine by optionally substituted benzo[b]thiophenes led to a number of derivatives with high antifungal activity. A series of benzo[b]thienyl compounds with the side chain at position 7 and different substituents at position 3 showed significantly increased activity against Candida albicans in vitro. In particular, the 3-chloro derivative with the allylamine side chain at position 7 (SDZ 87-469) proved to be the most potent allylamine antimycotic reported to this date. Two novel types of lead structures, the homopropargylamines and the benzylamines show very high activity in vitro.