Iminosugars as glycosyltransferase inhibitors: synthesis of polyhydroxypyrrolidines and their evaluation on chitin synthase activity.
Chitin synthase is an enzyme involved in the biosynthesis of chitin, a major structural component of the cell wall of many fungi. Since chitin is absent in vertebrates, chitin synthase has been envisaged as a valuable target in the search for new antifungal agents. In this report, a series of C-2 substituted polyhydroxypyrrolidines were designed and synthesized with the aim of mimicking the glycosylation involved at the transition state of the enzymatic reaction governed by chitin synthase. Some of these models displayed chitin synthase inhibition in the millimolar range. However, no significant antifungal activity was noted on a panel of fungal strains.
Gautier-Lefebvre
Isabelle
I
Laboratoire Réactions Sélectives et Applications UMR 6519, UFR Sciences-CNRS, BP 1039, 51687 Reims cedex 2, France.
Behr
Jean-Bernard
JB
Guillerm
Georges
G
Muzard
Murielle
M
D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002687:Chitin Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D005658:Fungi / Q000187:drug effects; D006031:Glycosylation; D050111:Imino Sugars / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D050111:Imino Sugars; D011760:Pyrrolidinones; D002687:Chitin Synthase