Synthesis, induced-fit docking investigations, and in vitro aldose reductase inhibitory activity of non-carboxylic acid containing 2,4-thiazolidinedione derivatives

Rosanna Maccari, Rosaria Ottanà, Rosella Ciurleo, Dietmar Rakowitz, Barbara Matuszczak, Christian Laggner, Thierry Langer

Research output: Contribution to journalArticlepeer-review

Abstract

In continuation of our studies, we here report a series of non-carboxylic acid containing 2,4-thiazolidinedione derivatives, analogues of previously synthesized carboxylic acids which we had found to be very active in vitro aldose reductase (ALR2) inhibitors. Although the replacement of the carboxylic group with the carboxamide or N-hydroxycarboxamide one decreased the in vitro ALR2 inhibitory effect, this led to the identification of mainly non-ionized derivatives with micromolar ALR2 affinity. The 5-arylidene moiety deeply influenced the activity of these 2,4-thiazolidinediones. Our induced-fit docking studies suggested that 5-(4-hydroxybenzylidene)-substituted derivatives may bind the polar recognition region of the ALR2 active site by means of the deprotonated phenol group, while their acetic chain and carbonyl group at position 2 of the thiazolidinedione ring form a tight net of hydrogen bonds with amino acid residues of the lipophilic specificity pocket of the enzyme.

Original languageEnglish
Pages (from-to)5840-5852
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume16
Issue number11
DOIs
Publication statusPublished - Jun 1 2008

Keywords

  • 2,4-Thiazolidinediones
  • Aldose reductase
  • Diabetes mellitus
  • Induced-fit docking

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

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