title: 5-Fluoroimidazo[4,5-b]pyridine Is a Privileged Fragment That Conveys Bioavailability to Potent Trypanosomal Methionyl-tRNA Synthetase Inhibitors.
abstract: Fluorination is a well-known strategy for improving the bioavailability of drug molecules. However, its impact on efficacy is not easily predicted. On the basis of inhibitor-bound protein crystal structures, we found a beneficial fluorination spot for inhibitors targeting methionyl-tRNA synthetase of Trypanosoma brucei. In particular, incorporating 5-fluoroimidazo[4,5-b]pyridine into inhibitors leads to central nervous system bioavailability and maintained or even improved efficacy.
authors.affiliation: Department of Biochemistry, University of Washington , 1705 N.E. Pacific Street, Seattle, Washington 98195, United States.
authors.forename: Zhongsheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, University of Washington , 1705 N.E. Pacific Street, Seattle, Washington 98195, United States.
authors.forename: Cho Yeow
authors.initials: CY
authors.lastname: Koh
authors.affiliation: Department of Medicine, Division of Allergy and Infectious Diseases, and the Center for Emerging and Re-emerging Infectious Diseases (CERID), University of Washington , 750 Republican Street, Seattle, Washington 98109, United States.
authors.forename: Ranae M
authors.initials: RM
authors.lastname: Ranade
authors.affiliation: Department of Biochemistry, University of Washington , 1705 N.E. Pacific Street, Seattle, Washington 98195, United States.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Shibata
authors.affiliation: Department of Medicine, Division of Allergy and Infectious Diseases, and the Center for Emerging and Re-emerging Infectious Diseases (CERID), University of Washington , 750 Republican Street, Seattle, Washington 98109, United States.
authors.forename: J Robert
authors.initials: JR
authors.lastname: Gillespie
authors.affiliation: Department of Medicine, Division of Allergy and Infectious Diseases, and the Center for Emerging and Re-emerging Infectious Diseases (CERID), University of Washington , 750 Republican Street, Seattle, Washington 98109, United States.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Hulverson
authors.affiliation: Department of Biochemistry, University of Washington , 1705 N.E. Pacific Street, Seattle, Washington 98195, United States.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Biochemistry, University of Washington , 1705 N.E. Pacific Street, Seattle, Washington 98195, United States.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Nguyen
authors.affiliation: Department of Chemistry, Bagley Hall, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Nagendar
authors.initials: N
authors.lastname: Pendem
authors.affiliation: Department of Chemistry, Bagley Hall, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
authors.affiliation: Department of Biochemistry, University of Washington , 1705 N.E. Pacific Street, Seattle, Washington 98195, United States.
authors.forename: Christophe L M J
authors.initials: CL
authors.lastname: Verlinde
authors.affiliation: Department of Biochemistry, University of Washington , 1705 N.E. Pacific Street, Seattle, Washington 98195, United States.
authors.forename: Wim G J
authors.initials: WG
authors.lastname: Hol
authors.affiliation: Department of Medicine, Division of Allergy and Infectious Diseases, and the Center for Emerging and Re-emerging Infectious Diseases (CERID), University of Washington , 750 Republican Street, Seattle, Washington 98109, United States.
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Buckner
authors.affiliation: Department of Biochemistry, University of Washington , 1705 N.E. Pacific Street, Seattle, Washington 98195, United States.
authors.forename: Erkang
authors.initials: E
authors.lastname: Fan
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005260:Female; D006801:Humans; D008718:Methionine-tRNA Ligase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D014353:Trypanosomiasis, African / Q000469:parasitology*
chemical_list: D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D011725:Pyridines; D014344:Trypanocidal Agents; D008718:Methionine-tRNA Ligase; C023666:pyridine
keywords: bioavailability; brain penetration; fluorination; human African trypanosomiasis; methionyl-tRNA synthetase