Cytoprotective Pyridinol Antioxidants as Potential Therapeutic Agents for Neurodegenerative and Mitochondrial Diseases

Publication Title

Bioorganic & Medicinal Chemistry

Document Type

Article

Publication Date

9-1-2014

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.

Recommended Citation

Mohammad Parvez Alam, Omar M. Khdour, Pablo M. Arce, Yana Chen, Basab Roy, Walter G. Johnson, Sriloy Dey, & Sidney M. Hecht, Cytoprotective Pyridinol Antioxidants as Potential Therapeutic Agents for Neurodegenerative and Mitochondrial Diseases, 22 Bioorganic & Medicinal Chem. 4935 (2014).

DOI

10.1016/j.bmc.2014.06.040

Volume

22

Issue

17

First Page

4395

Last Page

4947

This document is currently not available here.

Share

COinS