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

被引：5
作者：
Dai, Yumin [1 ,2 ]
Santiago-Rivera, Jose A. [1 ,2 ]
Hargett, Stefan [3 ,4 ]
Salamoun, Joseph M. [1 ,2 ]
Hoehn, Kyle L. [3 ,4 ,5 ]
Santos, Webster L. [1 ,2 ]
机构：
[1] Virginia Tech, Dept Chem, Blacksburg, VA 24061 USA
[2] Virginia Tech, Ctr Drug Discovery, Blacksburg, VA 24061 USA
[3] Univ Virginia, Dept Pharmacol, Charlottesville, VA 22908 USA
[4] Univ Virginia, Dept Med, Charlottesville, VA 22908 USA
[5] Univ New South Wales, Sch Biotechnol & Biomol Sci, Kensington, NSW 2033, Australia
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2022年 / 73卷
关键词：
PALLADIUM-CATALYZED AMIDATION; BIOLOGICAL EVALUATION; POTENT; DERIVATIVES; DISCOVERY; IMIDAZOPYRIDINES; IDENTIFICATION; IMIDAZOLES; INHIBITORS; MECHANISM;
D O I：
10.1016/j.bmcl.2022.128912
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
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 , 6 positions. Our studies suggest that both a 2-trifluoromethyl group and N-methylation are crucial for mitochondrial uncoupling capacity.
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页数：6
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