Probing the Influence of Linker Length and Flexibility in the Design and Synthesis of New Trehalase Inhibitors

Year: 2018

Authors: D’Adamio G., Forcella M., Fusi P., Parenti P., Matassini C., Ferhati X., Vanni C., Cardona F.

Autors Affiliation: Univ Florence, Dept Chem Ugo Schiff, Via Lastruccia 3-13, I-50019 Sesto Fiorentino, FI, Italy; Univ Milano Bicocca, Dept Biotechnol & Biosci, Piazza Sci 2, I-20126 Milan, Italy; Univ Milano Bicocca, Dept Earth & Environm Sci, Piazza Sci 1, I-20126 Milan, Italy; CNR INO, Via N Carrara 1, I-50019 Sesto Fiorentino, FI, Italy; Univ Bari, Consorzio Interuniv Nazl Ric Metodol & Proc Innov, I-70125 Bari, Italy.

Abstract: This work aims to synthesize new trehalase inhibitors selective towards the insect trehalase versus the porcine trehalase, in view of their application as potentially non-toxic insecticides and fungicides. The synthesis of a new pseudodisaccharide mimetic 8, by means of a stereoselective alpha-glucosylation of the key pyrrolizidine intermediate 13, was accomplished. The activity of compound 8 as trehalase inhibitor towards C. riparius trehalase was evaluated and the results showed that 8 was active in the mu M range and showed a good selectivity towards the insect trehalase. To reduce the overall number of synthetic steps, simpler and more flexible disaccharide mimetics 9-11 bearing a pyrrolidine nucleus instead of the pyrrolizidine core were synthesized. The biological data showed the key role of the linker chain’s length in inducing inhibitory properties, since only compounds 9 (alpha,beta-mixture), bearing a two-carbon atom linker chain, maintained activity as trehalase inhibitors. A proper change in the glucosyl donor-protecting groups allowed the stereoselective synthesis of the beta-glucoside 9 beta, which was active in the low micromolar range (IC50 = 0.78 mu M) and 12-fold more potent (and more selective) than 9 alpha towards the insect trehalase.

Journal/Review: MOLECULES

Volume: 23 (2)      Pages from: 436-1  to: 436-18

More Information: Ente Cassa di Risparmio di Firenze is acknowledged for a fellowship to GD (grant No. 2014/0303). CM thanks Accademia dei Lincei/Fondazione Donegani for a fellowship.
KeyWords: iminosugars; trehalase inhibitors; pseudodisaccharides; pyrrolizidines; pyrrolidines; glycosylation reaction
DOI: 10.3390/molecules23020436

Citations: 11
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