Anilinopyrazines as potential mitochondrial uncouplers

Bioorg Med Chem Lett. 2020 Apr 15;30(8):127057. doi: 10.1016/j.bmcl.2020.127057. Epub 2020 Feb 21.

Abstract

Mitochondrial protonophores transport protons through the mitochondrial inner membrane into the matrix to uncouple nutrient oxidation from ATP production thereby decreasing the proton motive force. Mitochondrial uncouplers have beneficial effects of decrease reactive oxygen species generation and have the potential for treating diseases such as obesity, neurodegenerative diseases, non-alcoholic fatty liver disease (NAFLD), diabetes, and many others. In this study, we report the structure-activity relationship profile of the pyrazine scaffold bearing substituted aniline rings. Our work indicates that a trifluoromethyl group is best at the para position while the trifluoromethoxy group is preferred in the meta position of the aniline rings of 2,3-substituted pyrazines. As proton transport and cycling requires the formation of a negative charge that has to traverse the mitochondrial membrane, a stabilizing internal hydrogen bond is a key feature for efficient mitochondrial uncoupling activity.

Keywords: Mitochondrial uncoupler; Oxidative phosphorylation; Protonophore; Pyrazine; Respiration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / chemistry
  • Aniline Compounds / pharmacology*
  • Dose-Response Relationship, Drug
  • Mitochondria / drug effects*
  • Molecular Structure
  • Pyrazines / chemistry
  • Pyrazines / pharmacology*
  • Reactive Oxygen Species / antagonists & inhibitors
  • Reactive Oxygen Species / metabolism
  • Structure-Activity Relationship
  • Uncoupling Agents / chemistry
  • Uncoupling Agents / pharmacology*

Substances

  • Aniline Compounds
  • Pyrazines
  • Reactive Oxygen Species
  • Uncoupling Agents
  • aniline