3-Hydroxypyrrolidine and (3,4)-dihydroxypyrrolidine derivatives: Inhibition of rat intestinal α-glucosidase

• Published in: Bioorganic chemistry Vol. 54; pp. 81 - 88
• Main Authors: Carreiro, Elisabete P., Louro, Patrícia, Adriano, Gizé, Guedes, Romina A., Vannuchi, Nicholas, Costa, Ana R., Antunes, Célia M.M., Guedes, Rita C., Burke, A.J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2014
• Subjects: 1-Benzyl-3,4-dihydroxypyrrolidine; 1-Benzyl-3-hydroxypyrrolidine; alpha-Glucosidases - metabolism; Animals; Artemia - drug effects; Artemia - growth & development; Cell Line; Cell Survival - drug effects; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Glycoside Hydrolase Inhibitors - chemical synthesis; Glycoside Hydrolase Inhibitors - chemistry; Glycoside Hydrolase Inhibitors - pharmacology; Humans; Intestines - enzymology; Models, Molecular; Molecular Structure; Pyrrolidines - chemical synthesis; Pyrrolidines - chemistry; Pyrrolidines - pharmacology; Rat intestinal cells; Rats; Small molecule inhibitor; Structure-Activity Relationship; α-Glucosidase; α-Glucosidase; 1-Benzyl-3,4-dihydroxypyrrolidine; Small molecule inhibitor; Rat intestinal cells; 1-Benzyl-3-hydroxypyrrolidine
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2014.04.007

[Display omitted] •The synthesis of a library of 13 chiral pyrrolidine derivatives.•Enzyme kinetics implied a mixed inhibition mode, corroborating our molecular docking studies.•Toxicological studies showed that they were non-toxic.•Molecular docking studies indicated the mechanism of competitive inhibition. Thirteen pyrrolidine-based iminosugar derivatives have been synthesized and evaluated for inhibition of α-glucosidase from rat intestine. The compounds studied were the non-hydroxy, mono-hydroxy and dihydroxypyrrolidines. All the compounds were N-benzylated apart from one. Four of the compounds had a carbonyl group in the 2,5-position of the pyrrolidine ring. The most promising iminosugar was the trans-3,4-dihydroxypyrrolidine 5 giving an IC50 of 2.97±0.046 and a KI of 1.18mM. Kinetic studies showed that the inhibition was of the mixed type, but predominantly competitive for all the compounds tested. Toxicological assay results showed that the compounds have low toxicity. Docking studies showed that all the compounds occupy the same region as the DNJ inhibitor on the enzyme binding site with the most active compounds establishing similar interactions with key residues. Our studies suggest that a rotation of ∼90° of some compounds inside the binding pocket is responsible for the complete loss of inhibitory activity. Despite the fact that activity was found only in the mM range, these compounds have served as simple molecular tools for probing the structural features of the enzyme, so that inhibition can be improved in further studies.