Glucopyranosylidene-spiro-imidazolinones, a New Ring System: Synthesis and Evaluation as Glycogen Phosphorylase Inhibitors by Enzyme Kinetics and X-ray Crystallography

Katalin E. Szabó, Efthimios Kyriakis, Anna Maria G. Psarra, Aikaterini G. Karra, Ádám Sipos, Tibor Docsa, George A. Stravodimos, Elisabeth Katsidou, Vassiliki T. Skamnaki, Panagiota G.V. Liggri, Spyros E. Zographos, Attila Mándi, Sándor Balázs Király, Tibor Kurtán, Demetres D. Leonidas, László Somsák

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Epimeric series of aryl-substituted glucopyranosylidene-spiro-imidazolinones, an unprecedented new ring system, were synthesized from the corresponding Schiff bases of O-perbenzoylated (gluculopyranosylamine)onamides by intramolecular ring closure of the aldimine moieties with the carboxamide group elicited by N-bromosuccinimide in pyridine. Test compounds were obtained by Zemplén O-debenzoylation. Stereochemistry and ring tautomers of the new compounds were investigated by NMR, time-dependent density functional theory (TDDFT)-electronic circular dichroism, and DFT-NMR methods. Kinetic studies with rabbit muscle and human liver glycogen phosphorylases showed that the (R)-imidazolinones were 14-216 times more potent than the (S) epimers. The 2-naphthyl-substituted (R)-imidazolinone was the best inhibitor of the human enzyme (Ki 1.7 μM) and also acted on HepG2 cells (IC50 177 μM). X-ray crystallography revealed that only the (R) epimers bound in the crystal. Their inhibitory efficacy is based on the hydrogen-bonding interactions of the carbonyl oxygen and the NH of the imidazolinone ring.

Original languageEnglish
Pages (from-to)6116-6136
Number of pages21
JournalJournal of Medicinal Chemistry
Volume62
Issue number13
DOIs
Publication statusPublished - Jun 18 2019

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Glucopyranosylidene-spiro-imidazolinones, a New Ring System: Synthesis and Evaluation as Glycogen Phosphorylase Inhibitors by Enzyme Kinetics and X-ray Crystallography'. Together they form a unique fingerprint.

  • Cite this

    Szabó, K. E., Kyriakis, E., Psarra, A. M. G., Karra, A. G., Sipos, Á., Docsa, T., Stravodimos, G. A., Katsidou, E., Skamnaki, V. T., Liggri, P. G. V., Zographos, S. E., Mándi, A., Király, S. B., Kurtán, T., Leonidas, D. D., & Somsák, L. (2019). Glucopyranosylidene-spiro-imidazolinones, a New Ring System: Synthesis and Evaluation as Glycogen Phosphorylase Inhibitors by Enzyme Kinetics and X-ray Crystallography. Journal of Medicinal Chemistry, 62(13), 6116-6136. https://doi.org/10.1021/acs.jmedchem.9b00356