Naturally occurring highly oxygenated piperidine, pyrrolidine and pyrrolizidine alkaloids and their derivatives are known to be potent glycosidase inhibitors. This class of compounds has great potential for the treatment of several pathological states in humans, and as pesticides. For this reason, the search for new and more active derivatives is still ongoing. In this respect, two sets of compounds have been synthesised: (i) trehalose mimics and (ii) N-spirofused bicyclic derivatives of 1-deoxynojirimycin, as permanent tetralkyl ammonium salts. (i) Trehalose α-D-glucopyranosyl-(1→1)-α-D-glucopyranoside (1, Figure 1) is present in a wide variety of organisms where it may serve as a source of energy and carbon. Trehalose analogs can find applications as selective trehalose processing enzymes inhibitors, such as trehalase. The design and synthesis of several trehalose mimics (compounds 2-8, Figure 1) will be presented. Preliminary evaluation of the inhibitory activity against porcine and insect trehalases will be reported. (ii) Alkaloid ability to be protonated in the catalytic site of glycosidase, generating an ammonium ion able to mimic the oxonium ion intermediate which participates in the hydrolysis of the glycosidic bond is a generally accepted explanation for their inhibitory activity. On this basis, different N-spirofused DNJ derivatives (9-11, Figure 1), with the additional ring with variable size and structural characteristics have been synthesised and evaluated for their inhibitory activity against commercial glycosidases.

1-Deoxynojirimycin (DNJ) and pyrrolizidine derivatives as glycosidase inhibitors

251st National Meeting (2016)

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