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

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

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: santosw@vt.edu.
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.

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