Conversion of oxadiazolo[3,4-b]pyrazines to imidazo[4,5-b]pyrazines via a tandem reduction-cyclization sequence generates new mitochondrial uncouplers

  • Bioorg Med Chem Lett. 2022 Oct 1:73:128912. doi: 10.1016/j.bmcl.2022.128912.
Yumin Dai  1 ,  José A Santiago-Rivera  1 ,  Stefan Hargett  2 ,  Joseph M Salamoun  1 ,  Kyle L Hoehn  3 ,  Webster L Santos  4
Affiliations
  • 1. Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, United States.
  • 2. Departments of Pharmacology and Medicine, University of Virginia, Charlottesville, VA 22908, United States.
  • 3. Departments of Pharmacology and Medicine, University of Virginia, Charlottesville, VA 22908, United States; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, NSW 2033, Australia.
  • 4. Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, United States. Electronic address: [email protected].
PMID: 35907607 DOI: 10.1016/j.bmcl.2022.128912
Abstract

We report new mitochondrial uncouplers derived from the conversion of [1,2,5]oxadiazolo[3,4-b]pyrazines to 1H-imidazo[4,5-b]pyrazines. The in situ Fe-mediated reduction of the oxadiazole fragment followed by cyclization gave access to imidazopyrazines in moderate to good yields. A selection of orthoesters also allowed functionalization on the 2-position of the imidazole ring. This method afforded a variety of imidazopyrazine derivatives with varying substitution on the 2, 5 and 6 positions. Our studies suggest that both a 2-trifluoromethyl group and N-methylation are crucial for mitochondrial uncoupling capacity.