title: Design and synthesis of potent substrate-based inhibitors of the Trypanosoma cruzi dihydroorotate dehydrogenase.
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 Kiappvalues 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.
authors.affiliation: 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.
authors.forename: Daniel Ken
authors.initials: DK
authors.lastname: Inaoka
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Iida
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hashimoto
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tabuchi
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Takefumi
authors.initials: T
authors.lastname: Kuranaga
authors.affiliation: School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki 852-8523, Japan.
authors.forename: Emmanuel Oluwadare
authors.initials: EO
authors.lastname: Balogun
authors.affiliation: Systems and Structural Biology Center, RIKEN, Tsurumi, Yokohama 230-0045, Japan.
authors.forename: Teruki
authors.initials: T
authors.lastname: Honma
authors.affiliation: Systems and Structural Biology Center, RIKEN, Tsurumi, Yokohama 230-0045, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Tanaka
authors.affiliation: Graduate School of Science and Technology, Kyoto Institute of Technology, Kyoto 606-8585, Japan.
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Harada
authors.affiliation: Department of Molecular and Cellular Parasitology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nara
authors.affiliation: 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.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kita
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan. Electronic address: inoue@mol.f.u-tokyo.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Inoue
mesh_terms: D014355:Chagas Disease / Q000188:drug therapy / Q000469:parasitology; D000090722:Dihydroorotate Dehydrogenase; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D009963:Orotic Acid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology
chemical_list: D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D009963:Orotic Acid; D044925:Oxidoreductases Acting on CH-CH Group Donors