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Probing the Influence of Linker Length and Flexibility in the Design and Synthesis of New Trehalase Inhibitors
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-glucosyla...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017881/ https://www.ncbi.nlm.nih.gov/pubmed/29462919 http://dx.doi.org/10.3390/molecules23020436 |
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author | D’Adamio, Giampiero Forcella, Matilde Fusi, Paola Parenti, Paolo Matassini, Camilla Ferhati, Xhenti Vanni, Costanza Cardona, Francesca |
author_facet | D’Adamio, Giampiero Forcella, Matilde Fusi, Paola Parenti, Paolo Matassini, Camilla Ferhati, Xhenti Vanni, Costanza Cardona, Francesca |
author_sort | D’Adamio, Giampiero |
collection | PubMed |
description | 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 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 (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 (IC(50) = 0.78 μM) and 12-fold more potent (and more selective) than 9α towards the insect trehalase. |
format | Online Article Text |
id | pubmed-6017881 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-60178812018-11-13 Probing the Influence of Linker Length and Flexibility in the Design and Synthesis of New Trehalase Inhibitors D’Adamio, Giampiero Forcella, Matilde Fusi, Paola Parenti, Paolo Matassini, Camilla Ferhati, Xhenti Vanni, Costanza Cardona, Francesca Molecules Article 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 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 (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 (IC(50) = 0.78 μM) and 12-fold more potent (and more selective) than 9α towards the insect trehalase. MDPI 2018-02-16 /pmc/articles/PMC6017881/ /pubmed/29462919 http://dx.doi.org/10.3390/molecules23020436 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article D’Adamio, Giampiero Forcella, Matilde Fusi, Paola Parenti, Paolo Matassini, Camilla Ferhati, Xhenti Vanni, Costanza Cardona, Francesca Probing the Influence of Linker Length and Flexibility in the Design and Synthesis of New Trehalase Inhibitors |
title | Probing the Influence of Linker Length and Flexibility in the Design and Synthesis of New Trehalase Inhibitors |
title_full | Probing the Influence of Linker Length and Flexibility in the Design and Synthesis of New Trehalase Inhibitors |
title_fullStr | Probing the Influence of Linker Length and Flexibility in the Design and Synthesis of New Trehalase Inhibitors |
title_full_unstemmed | Probing the Influence of Linker Length and Flexibility in the Design and Synthesis of New Trehalase Inhibitors |
title_short | Probing the Influence of Linker Length and Flexibility in the Design and Synthesis of New Trehalase Inhibitors |
title_sort | probing the influence of linker length and flexibility in the design and synthesis of new trehalase inhibitors |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017881/ https://www.ncbi.nlm.nih.gov/pubmed/29462919 http://dx.doi.org/10.3390/molecules23020436 |
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