Inhibitors of the fungal cell wall. Synthesis of 4-aryl-4-N-arylamine-1- butenes and related compounds with inhibitory activities on β(1-3) glucan and chitin synthases

Abstract

As part of our project devoted to the search for antifungal agents, which act via a selective mode of action, we synthesized a series of new 4- aryl- or 4-alkyl-N-arylamine-1-butenes and transformed some of them into 2- substituted 4-methyl-tetrahydroquinolines and quinolines by using a novel three-step synthesis. Results obtained in agar dilution assays have shown that 4-aryl homoallylamines not possessing halogen in their structures, tetrahydroquinolines and quinolines, display a range of antifungal properties in particular against Epidermophyton floccosum and Microsporum canis. Regarding the mode of action, all active compounds showed in vitro inhibitory activities against β(1-3) glucan-synthase and mainly against chitin- synthase. These enzymes catalyze the synthesis of β(1-3) glucan and chitin, respectively, major polymers of the fungal cell wall. Since fungal but not mammalian cells are encased in a cell wall, its inhibition may represent a useful mode of action for these antifungal compounds.