Structure-activity relationships of furazano[3,4-b]pyrazines as mitochondrial uncouplers

Brandon M Kenwood; Joseph A Calderone; Evan P Taddeo; Kyle L Hoehn; Webster L Santos

doi:10.1016/j.bmcl.2015.06.040

Structure-activity relationships of furazano[3,4-b]pyrazines as mitochondrial uncouplers

Bioorg Med Chem Lett. 2015 Nov 1;25(21):4858-4861. doi: 10.1016/j.bmcl.2015.06.040. Epub 2015 Jun 16.

Authors

Brandon M Kenwood¹, Joseph A Calderone², Evan P Taddeo¹, Kyle L Hoehn³, Webster L Santos⁴

Affiliations

¹ Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
² Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, USA.
³ Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA; Department of Medicine, University of Virginia, Charlottesville VA 22908, USA; Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA; Emily Couric Clinical Cancer Center, University of Virginia, Charlottesville, VA 22908, USA; Department of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, NSW 2052, Australia.
⁴ Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, USA. Electronic address: santosw@vt.edu.

Abstract

Chemical mitochondrial uncouplers are lipophilic weak acids that transport protons into the mitochondrial matrix via a pathway that is independent of ATP synthase, thereby uncoupling nutrient oxidation from ATP production. These uncouplers have potential for the treatment of diseases such as obesity, Parkinson's disease, and aging. We have previously identified a novel mitochondrial protonophore, named BAM15, which stimulates mitochondrial respiration across a broad dosing range compared to carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP). Herein, we report our investigations on the structure-activity relationship profile of BAM15. Our studies demonstrate the importance of the furazan, pyrazine, and aniline rings as well as pKa in maintaining its effective protonophore activity.

Keywords: Mitochondrial bioenergetics; Mitochondrial uncoupler; Protonophore; Pyrazines; Structure–activity relationships.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / metabolism
Dose-Response Relationship, Drug
Mitochondria / drug effects*
Mitochondria / metabolism
Molecular Structure
Oxidation-Reduction / drug effects
Pyrazines / chemical synthesis
Pyrazines / chemistry*
Pyrazines / pharmacology*
Structure-Activity Relationship
Uncoupling Agents / chemical synthesis
Uncoupling Agents / chemistry*
Uncoupling Agents / pharmacology*

Substances

Pyrazines
Uncoupling Agents
furazano(3,4-b)pyrazine
Adenosine Triphosphate

Grants and funding

T32 GM007055/GM/NIGMS NIH HHS/United States