Fungal biotransformations of anticholinesterase norbelladine derivatives to obtain new products and mimic mammalian metabolism

Abstract

Norbelladine is the natural precursor of all alkaloids of the Amaryllidaceae family. These compounds have been reported to exert interesting biological activities. Particularly, galantamine is currently used in the palliative treatment of Alzheimer’s disease for its cholinergic effect. The biotransformation of two norbelladine analogues exhibiting anticholinesterase activity was studied using 11 fungi belonging to Aspergillus , Rhizopus , Cunninghamella and Fusarium genera. The substrates were refractory to biotransformation by all fungi screened, except by A. clavatus . Based on GC-MS analyses, we demonstrated that its enzymes were able to catalyse the oxidative cleavage of the C-N bond of the secondary amine of 4’- O -methylnorbelladine. On the other hand, the hindered phenolic hydroxy group at the 3’ position of the brominated derivative was regioselectively methylated. The latter compound was chemically synthesised for better characterisation and the biological assays showed that this metabolite exerted a lower inhibition of BChE and lost the anti-AChE activity. The metabolic pathways involved here were useful to mimic phase I and II xenobiotic metabolism in mammals and thus predict the products that could be formed. A new source of biocatalytic tools to obtain new protoalkaloid derivatives was also discovered. • Norbelladine derivatives have shown promising anticholinesterase activities. • Fungal model is useful to predict phase I and II metabolism in mammals. • Norbelladine analogues remained untransformed with most of the fungi tested. • Two norbelladine analogues were metabolised by Aspergillus clavatus . • Biotransformation of the brominated derivative led to loss of anti-AChE activity.