Design and Synthesis of Potent Substrate-based Inhibitors of the Trypanosoma cruzi Dihydroorotate Dehydrogenase

Publication date: Available online 9 January 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Daniel Ken Inaoka, Maiko Iida, Satoshi Hashimoto, Toshiyuki Tabuchi, Takefumi Kuranaga, Emmanuel Oluwadare Balogun, Teruki Honma, Akiko Tanaka, Shigeharu Harada, Takeshi Nara, Kiyoshi Kita, Masayuki Inoue
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 Ki^app 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.

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