title: Evaluation of substituted ebselen derivatives as potential trypanocidal agents.
abstract: Human African trypanosomiasis is a disease of sub-Saharan Africa, where millions are at risk for the illness. The disease, commonly referred to as African sleeping sickness, is caused by an infection by the eukaryotic pathogen, Trypanosoma brucei. Previously, a target-based high throughput screen revealed ebselen (EbSe), and its sulfur analog, EbS, to be potent in vitro inhibitors of the T. brucei hexokinase 1 (TbHK1). These molecules also exhibited potent trypanocidal activity in vivo. In this manuscript, we synthesized a series of sixteen EbSe and EbS derivatives bearing electron-withdrawing carboxylic acid and methyl ester functional groups, and evaluated the influence of these substituents on the biological efficacy of the parent scaffold. With the exception of one methyl ester derivative, these modifications ablated or blunted the potent TbHK1 inhibition of the parent scaffold. Nonetheless, a few of the methyl ester derivatives still exhibited trypanocidal effects with single-digit micromolar or high nanomolar EC50values.
authors.affiliation: Department of Chemistry, 467 Hunter Laboratories, Clemson University, Clemson, SC 29634, USA.
authors.forename: Heeren M
authors.initials: HM
authors.lastname: Gordhan
authors.affiliation: Eukaryotic Pathogens Innovation Center, Department of Genetics and Biochemistry, 249 Life Sciences Building, Clemson University, Clemson, SC 29634, USA.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Patrick
authors.affiliation: Department of Chemistry, 467 Hunter Laboratories, Clemson University, Clemson, SC 29634, USA.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Swasy
authors.affiliation: Eukaryotic Pathogens Innovation Center, Department of Genetics and Biochemistry, 249 Life Sciences Building, Clemson University, Clemson, SC 29634, USA.
authors.forename: Amber L
authors.initials: AL
authors.lastname: Hackler
authors.affiliation: Department of Chemistry, 467 Hunter Laboratories, Clemson University, Clemson, SC 29634, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Anayee
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin, 777 Highland Ave., Madison, WI 53705-2222, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Golden
authors.affiliation: Eukaryotic Pathogens Innovation Center, Department of Genetics and Biochemistry, 249 Life Sciences Building, Clemson University, Clemson, SC 29634, USA. Electronic address: jmorri2@clemson.edu.
authors.forename: James C
authors.initials: JC
authors.lastname: Morris
authors.affiliation: Department of Chemistry, 467 Hunter Laboratories, Clemson University, Clemson, SC 29634, USA. Electronic address: dwhiteh@clemson.edu.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Whitehead
mesh_terms: D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001393:Azoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D054833:Isoindoles; D015394:Molecular Structure; D016566:Organoselenium Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects*
chemical_list: D000981:Antiprotozoal Agents; D001393:Azoles; D054833:Isoindoles; D016566:Organoselenium Compounds; D014344:Trypanocidal Agents; C042986:ebselen
keywords: Ebselen; Hexokinases; Trypanosomes