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

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

doi:10.1016/j.bmc.2017.01.009

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

Bioorg Med Chem. 2017 Feb 15;25(4):1465-1470. doi: 10.1016/j.bmc.2017.01.009. Epub 2017 Jan 9.

Affiliations

¹ School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki 852-8523, Japan; Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
² Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
³ School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki 852-8523, Japan.
⁴ Systems and Structural Biology Center, RIKEN, Tsurumi, Yokohama 230-0045, Japan.
⁵ Graduate School of Science and Technology, Kyoto Institute of Technology, Kyoto 606-8585, Japan.
⁶ Department of Molecular and Cellular Parasitology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
⁷ Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan. Electronic address: inoue@mol.f.u-tokyo.ac.jp.

PMID: 28118956
DOI: 10.1016/j.bmc.2017.01.009

Abstract

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 K_i^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.

MeSH terms

Chagas Disease / drug therapy
Chagas Disease / parasitology
Dihydroorotate Dehydrogenase
Dose-Response Relationship, Drug
Drug Design*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Molecular Structure
Orotic Acid / chemical synthesis
Orotic Acid / chemistry
Orotic Acid / pharmacology*
Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors*
Oxidoreductases Acting on CH-CH Group Donors / metabolism
Structure-Activity Relationship
Trypanosoma cruzi / drug effects*
Trypanosoma cruzi / enzymology

Substances

Dihydroorotate Dehydrogenase
Enzyme Inhibitors
Orotic Acid
Oxidoreductases Acting on CH-CH Group Donors