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Molecules 2018, 23(2), 436; https://doi.org/10.3390/molecules23020436

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

1
Department of Chemistry ‘Ugo Schiff’, University of Florence, via della Lastruccia 3-13, I-50019 Sesto Fiorentino (FI), Italy
2
Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy
3
Department of Earth and Environmental Sciences, University of Milano-Bicocca, Piazza della Scienza 1, 20126 Milano, Italy
4
Associated with CNR-INO, Via N. Carrara 1, I-50019 Sesto Fiorentino (FI), Italy
5
Associated with Consorzio Interuniversitario Nazionale di ricerca in Metodologie e Processi Innovativi di Sintesi (CINMPIS), Università di Bari, 70125 Bari, Italy
*
Authors to whom correspondence should be addressed.
Received: 30 January 2018 / Revised: 12 February 2018 / Accepted: 14 February 2018 / Published: 16 February 2018
(This article belongs to the Special Issue Glycomimetics: Design, Synthesis and Therapeutic Applications)
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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 α-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 μM range and showed a good selectivity towards the insect trehalase. To reduce the overall number of synthetic steps, simpler and more flexible disaccharide mimetics 911 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 (α,β-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 β-glucoside 9β, which was active in the low micromolar range (IC50 = 0.78 μM) and 12-fold more potent (and more selective) than 9α towards the insect trehalase. View Full-Text
Keywords: iminosugars; trehalase inhibitors; pseudodisaccharides; pyrrolizidines; pyrrolidines; glycosylation reaction iminosugars; trehalase inhibitors; pseudodisaccharides; pyrrolizidines; pyrrolidines; glycosylation reaction
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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D’Adamio, G.; Forcella, M.; Fusi, P.; Parenti, P.; Matassini, C.; Ferhati, X.; Vanni, C.; Cardona, F. Probing the Influence of Linker Length and Flexibility in the Design and Synthesis of New Trehalase Inhibitors. Molecules 2018, 23, 436.

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