Camiglibose

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′ax, 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.

α- and β-glucosidases are postulated to be a very attractive therapeutic target since they catalyze the cleavage of glycosidic bonds releasing glucose from the non-reducing end of an oligo- or polysaccharide chain involved in glycoprotein biosynthesis.Glucosidase inhibitors are currently of interest owing to their promising therapeutic potential in the treatment of disorders such as diabetes, AIDS, metastatic cancer and lysosomal storage diseases.α-Glucosidases can be divided into two groups, family I and family II, and the appropriate choice of the homolog enzyme to structure-based drug design purposes could prove to be successful in the development of new pharmaceuticals.In this work, we have found the highest identity of the human enzyme with the rat intestinal sucrase, when compared to other homolog proteins commonly used in biol. assays, such as Saccharomyces cerevisiae α-glucosidase.Consequently, we have built and validated a 3D model for this rat enzyme, and addnl. performed docking simulations of well-known glucosidase inhibitors as well as pharmacophore modeling and mol. interaction fields studies in order to establish the most relevant structural features of inhibitors and enzyme for inhibitory activity.Using this mixed methodol. we have proposed how the reported inhibitors may interact at mol. level as well as discussed the role of key α-glucosidase residues in the active site, in order to design novel proposals of inhibitors.