Design, synthesis, molecular docking and crystal structure prediction of new azasugar analogues of α-glucosidase inhibitors
European Journal of Organic Chemistry, ISSN: 1434-193X, Vol: 2011, Issue: 36, Page: 7278-7287
2011
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Article Description
This work deals with the design and synthesis of α-glucosidase inhibitors. In order to perform this task, a molecular docking study was carried out with the N-terminal catalytic subunit of human maltase glucoamylase, which evidenced a partially empty, hydrophobic part of the docking pocket. As a consequence, we decided to improve the docking abilities of the known α-glucosidase inhibitor MDL 73495 and carried out the synthesis of new N-glycosyl-derived analogues. The addition of a hydrophobic methyl group at C-5′, the concomitant elimination of the equatorial hydroxy group, the inversion of the configuration at C-4 in the sugar unit and the substitution of the hydroxy group at C-6′ with an amino group led to 6′-deoxy-6′-amino-6a. This compound showed the lowest in silico binding affinity among a set of compounds, whose experimental activity has been reported. Bearing these results in mind, we synthesized 6a and 6b. Because of the lack of large amounts of products, which are necessary to perform crystallization, the crystal structures of 6a and 6b were predicted in silico. These can be considered as models for future X-ray powder diffraction characterization of these two compounds. We describe the design and synthesis of a new N-glycosyl-derived analogue of MDL 73945, as a potential α-glucosidase inhibitor, with a K value of 64 nM. A more potent 6′-deoxy-6′-amino derivative has alsobeen isolated. Crystal structures of the compounds have been predicted in silico, which can be considered as models for future X-ray powder diffraction characterization of the compounds. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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