Five-membered iminocyclitol a-glucosidase inhibitors: Synthetic,biological scre...

• Author(s): Guerreiro, L ; Carreiro, E ; Fernandes, L ; Cardote, T ; Moreira, R ; Caldeira, A Teresa ; Guedes, R ; Burke, A J
• Date: 2013
• Persistent ID: http://hdl.handle.net/10174/10266
• Origin: Repositório Científico da Universidade de Évora
• Subject(s): Iminocyclitol; Small molecule inhibitor; a-Glucosidase; Enantiopure compound; (3,4)-Dihydroxypyrrolidine
• Document Type: Article
• Language: English

Description

The design and synthesis of a small library of pyrrolidine iminocyclitol inhibitors with a structural similarity to 1,4-dideoxy-1,4-imino-D-arabitol (DAB-1) is reported. This library was specifically designed to gain a better insight into the mechanism of inhibition of glycosidases by polyhydroxylated pyrrolidines or iminocyclitols. Pyrrolidine-3,4-diol 15a and pyrrolidine-3,4-diol diacetate 15b had emerged as the most potent a-glucosidase inhibitors in the series. Docking studies performed with an homology model of a-glucosidase disclosed binding poses for compounds 15a, 15b, 16a, and 16a0 occupying the same region as the NH group of the terminal ring of acarbose and suggest a closer and stronger binding of compound 15a and 15b with the enzyme active site residues. Our studies indicate that 2 or 5-hydroxyl substituents appear to be vital for high inhibitory activity.