title: Five-membered iminocyclitol α-glucosidase inhibitors: synthetic, biological screening and in silico studies.
abstract: 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 α-glucosidase inhibitors in the series. Docking studies performed with an homology model of α-glucosidase disclosed binding poses for compounds 15a, 15b, 16a, and 16a' 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.
authors: Departamento de Química and Centro de Química de Évora, Universidade de Évora, Rua Romão Ramalho, 59, 7000 Évora, Portugal.
authors: Luis R
authors: LR
authors: Guerreiro
authors: Elisabete P
authors: EP
authors: Carreiro
authors: Luis
authors: L
authors: Fernandes
authors: Teresa A F
authors: TA
authors: Cardote
authors: Rui
authors: R
authors: Moreira
authors: Ana T
authors: AT
authors: Caldeira
authors: Rita C
authors: RC
authors: Guedes
authors: A J
authors: AJ
authors: Burke
mesh_terms: D054812:Cyclitols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D065089:Glycoside Hydrolase Inhibitors; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D000520:alpha-Glucosidases / Q000737:chemistry / Q000378:metabolism
chemical_list: D054812:Cyclitols; D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D011759:Pyrrolidines; D000520:alpha-Glucosidases