Synthesis, Biological Evaluation and Docking Studies of Casuarine Analogues: Effects of Structural Modifications at Ring B on Inhibitory Activity Towards Glucoamylase

We report the total synthesis of a series of pyrrolizidine analogues of casuarine (1) and their 6‐O‐α‐glucoside derivatives. The synthetic strategy is based on a totally regio‐ and stereoselective 1,3‐dipolar cycloaddition of suitably substitutedalkenes and a carbohydrate‐based nitrone. We also report the evaluation of the biological activity of casuarine and its derivatives towards a wide range of glycosidases and a molecular modeling study focused on glucoamylase (GA) in which the binding modes of the newly synthesized compounds within the enzyme cavity are investigated. The results highlight the prominent structural features of casuarine and its derivatives that make them selective glucoamylase inhibitors. A series of casuarine derivatives structurally modified at ring B of the pyrrolizidine nucleus have been synthesized and found to be selective inhibitors of fungal amyloglucosidase. The nature of the interactions between the enzyme active site and the prepared molecules has been investigated by molecular docking simulations.