Synthesis and antifungal activity of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthalenemethanamine (SF 86-327) and related allylamine derivatives with enhanced oral activity

Abstract

The allylamine derivatives [N-methyl-N-2,4-nonadiynyl-1-naphthalenemethanamine, (E)-N-methyl-N-2-nonen-4-ynyl-1-naphthalenemethanamine, (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthalenemethanamine, (E,E)-N-methyl-N-2,4-nonadienyl-1-naphthalenemethanamine and (E)-N-methyl-N-4-nonen-2-ynyl-1-naphthalenemethanamine] are a new class of synthetic antifungal agents inhibiting fungal squalene epoxidase. A new subclass, which features an acetylene group conjugated with the allylamine double bond, is characterized by enhanced antifungal activity, especially on oral treatment of guinea pig dermatophytoses [Trichophyton mentagrophytes, Aspergillus fumigatus and Candida albicans]. Increased branching of the alkyl group next to the triple bond led to the tert-butylacetylene derivative SF 86-327, a compound with strikingly increased activity in vitro and in vivo, which is now under clinical evaluation. Versatile synthetic routes, comparative biological data and structure-activity relationships are presented.