Cytoprotective pyridinol antioxidants as potential therapeutic agents for neurodegenerative and mitochondrial diseases

Mohammad Parvez Alam, Omar Khdour, Pablo M. Arce, Yana Chen, Basab Roy, Walter G. Johnson, Sriloy Dey, Sidney Hecht

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

As part of our ongoing efforts to identify compounds having potential utility in treating neurodegenerative and mitochondrial disorders, a series of pyridinol analogues have been prepared. The synthetic route employed for the preparation of the new analogues is different, and considerably more efficient, than that used in previously reported studies. The new route yields a pair of pyridinol regioisomers that can be readily separated and evaluated. Their ability to quench lipid peroxidation and reactive oxygen species (ROS), and to preserve mitochondrial membrane potential (Δψm) and support ATP synthesis is reported. The optimal side chain length was found to be 16 carbon atoms. The metabolic stability of those compounds having optimal biological activities was evaluated in vitro using bovine liver microsomes. The omission of any side chain hydroxyl group and introduction of an azetidine moiety at position 6 of the pyridinol redox core (8 and 9) increased their microsomal stability as compared to the exocyclic dimethylamino group. The favorable metabolic stability conferred by the azetidine moiety in compounds 8 and 9 makes these compounds excellent candidates for further evaluation.

Original languageEnglish (US)
Pages (from-to)4935-4947
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number17
DOIs
StatePublished - Sep 1 2014

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Keywords

  • Cytoprotection
  • Lipid peroxidation
  • Microsomal stability
  • Mitochondria
  • Reactive oxygen species

ASJC Scopus subject areas

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

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