Conversion of oxadiazolo[3, 4-b]pyrazines to imidazo[4, 5-b]pyrazines via a tandem reduction-cyclization sequence generates new mitochondrial uncouplers. (1st October 2022)

• Record Type: Journal Article
• Authors: Dai, Yumin; Santiago-Rivera, José A.; Hargett, Stefan; Salamoun, Joseph M.; Hoehn, Kyle L.; Santos, Webster L.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 73(2022)
• Publication Date: 2022-10-01
• Subjects: Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.128912
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: We report new mitochondrial uncouplers derived from the conversion of [1, 2, 5]oxadiazolo[3, 4- b ]pyrazines to 1 H -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.