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

As part of our project devoted to the search for antifungal agents, which a ct via a selective mode of action, we synthesized a series of new 4-aryl- o r 4-alkyl-N-arylamine-1-butenes and transformed some of them into 2-substit uted 4-methyl-tetrahydroquinolines and quinolines by using a novel three-st ep synthesis. Results obtained in agar dilution assays have shown that 4-ar yl homoallylamines not possessing halogen in their structures, tetrahydroqu inolines and quinolines, display a range of antifungal properties in partic ular against Epidermophyton floccosum and Microsporum canis. Regarding the mode of action, all active compounds showed in vitro inhibitory activities against beta(1-3) glucan-synthase and mainly against chitin-synthase. These enzymes catalyze the synthesis of beta(1-3) glucan and chitin, respectivel y, major polymers of the fungal cell wall. Since fungal but not mammalian c ells are encased in a cell wall, its inhibition may represent a useful mode of action for these antifungal compounds. (C) 2000 Elsevier Science Ltd. A ll rights reserved.