Design and synthesis of potent substrate-based inhibitors of the Trypanosoma cruzi dihydroorotate dehydrogenase

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• 作者：Daniel Ken Inaoka^a ; ^b ; Maiko Iida^c ; Satoshi Hashimoto^c ; Toshiyuki Tabuchi^c ; Takefumi Kuranaga^c ; Emmanuel Oluwadare Balogun^a ; Teruki Honma^d ; Akiko Tanaka^d ; Shigeharu Harada^e ; Takeshi Nara^f ; Kiyoshi Kita^a ; ^b ; Masayuki Inoue^c ; ^{inoue@mol.f.u-tokyo.ac.jp}
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2017
• 出版时间：15 February 2017
• 年：2017
• 卷：25
• 期：4
• 页码：1465-1470
• 全文大小：924 K
• 卷排序：25

文摘

Chagas disease, caused by the parasitic protozoan Trypanosoma cruzi, is the leading cause of heart disease in Latin America. T. cruzi dihydroorotate dehydrogenase (DHODH), which catalyzes the production of orotate, was demonstrated to be essential for T. cruzi survival, and thus has been considered as a potential drug target to combat Chagas disease. Here we report the design and synthesis of 75 compounds based on the orotate structure. A comprehensive structure-activity relationship (SAR) study revealed two 5-substituted orotate analogues (5u and 5v) that exhibit Kiapp values of several ten nanomolar level and a selectivity of more than 30,000-fold over human DHODH. The information presented here will be invaluable in the search for next-generation drug leads for Chagas disease.