title: Structure mechanism insights and the role of nitric oxide donation guide the development of oxadiazole-2-oxides as therapeutic agents against schistosomiasis.
abstract: Schistosomiasis is a chronic parasitic disease affecting hundreds of millions of individuals worldwide. Current treatment depends on a single agent, praziquantel, raising concerns of emergence of resistant parasites. Here, we continue our explorations of an oxadiazole-2-oxide class of compounds we recently identified as inhibitors of thioredoxin glutathione reductase (TGR), a selenocysteine-containing flavoenzyme required by the parasite to maintain proper cellular redox balance. Through systematic evaluation of the core molecular structure of this chemotype, we define the essential pharmacophore, establish a link between the nitric oxide donation and TGR inhibition, determine the selectivity for this chemotype versus related reductase enzymes, and present evidence that these agents can be modified to possess appropriate drug metabolism and pharmacokinetic properties. The mechanistic link between exogenous NO donation and parasite injury is expanded and better defined. The results of these studies verify the utility of oxadiazole-2-oxides as novel inhibitors of TGR and as efficacious antischistosomal agents.
authors.affiliation: NIH Chemical Genomics Center, National Human Genome Research Institute, NIH, 9800 Medical Center Drive, MSC 3370, Bethesda, Maryland 20892-3370, USA.
authors.forename: Ganesha
authors.initials: G
authors.lastname: Rai
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Sayed
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Lea
authors.forename: Hans F
authors.initials: HF
authors.lastname: Luecke
authors.forename: Harinath
authors.initials: H
authors.lastname: Chakrapani
authors.forename: Stefanie
authors.initials: S
authors.lastname: Prast-Nielsen
authors.forename: Ajit
authors.initials: A
authors.lastname: Jadhav
authors.forename: William
authors.initials: W
authors.lastname: Leister
authors.forename: Min
authors.initials: M
authors.lastname: Shen
authors.forename: James
authors.initials: J
authors.lastname: Inglese
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Austin
authors.forename: Larry
authors.initials: L
authors.lastname: Keefer
authors.forename: Elias S J
authors.initials: ES
authors.lastname: Arnér
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
authors.forename: David J
authors.initials: DJ
authors.lastname: Maloney
authors.forename: David L
authors.initials: DL
authors.lastname: Williams
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
mesh_terms: D000818:Animals; D001682:Biological Availability; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000737:chemistry; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry; D009569:Nitric Oxide / Q000737:chemistry*; D010069:Oxadiazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011487:Protein Conformation; D051381:Rats; D012547:Schistosoma / Q000187:drug effects; D012552:Schistosomiasis / Q000188:drug therapy* / Q000201:enzymology; D012556:Schistosomicides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D012995:Solubility; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: C528141:1,2,5-oxadiazole 2-oxide; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D010069:Oxadiazoles; D012556:Schistosomicides; D009569:Nitric Oxide; D009247:NADH, NADPH Oxidoreductases; C466433:thioredoxin glutathione reductase