title: Trypanocidal activity of aziridinyl nitrobenzamide prodrugs.
abstract: The trypanocidal agents nifurtimox and benznidazole both function as prodrugs and must undergo enzyme-mediated activation, a reaction catalyzed by type I nitroreductase (NTR). In the search for new parasitic therapies, we have utilized this finding to investigate whether aziridinyl nitrobenzamide derivatives have activity against bloodstream-form Trypanosoma brucei and Trypanosoma cruzi amastigotes, parasite stages that replicate in the mammalian host. For T. cruzi drug screening, we generated trypanosomes that expressed the luciferase reporter gene and optimized a mammalian infection model in a 96-well plate format. A subset of compounds having a 5-(aziridin-1-yl)-2,4-dinitrobenzyl structure was shown to be metabolized by purified T. brucei NTR and when screened against both parasite life cycle stages displayed significant growth-inhibitory properties: the most potent compounds generated 50% inhibitory concentrations of <1 μM. The trypanocidal activity was shown to be NTR specific, since parasites overexpressing this enzyme were hypersensitive to the aziridinyl dinitrobenzyl agents. We conclude that members of the aziridinyl nitrobenzamide class of nitroheterocycles provide new lead structures that have the potential to treat trypanosomal infections.
authors.affiliation: Queen Mary Pre-Clinical Drug Discovery Group, School of Biological and Chemical Sciences, Queen Mary University of London, London E1 4NS, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Bot
authors.forename: Belinda S
authors.initials: BS
authors.lastname: Hall
authors.forename: Noosheen
authors.initials: N
authors.lastname: Bashir
authors.forename: Martin C
authors.initials: MC
authors.lastname: Taylor
authors.forename: Nuala A
authors.initials: NA
authors.lastname: Helsby
authors.forename: Shane R
authors.initials: SR
authors.lastname: Wilkinson
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D020128:Inhibitory Concentration 50; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000472:pathogenicity; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000472:pathogenicity; D014352:Trypanosomiasis / Q000188:drug therapy / Q000469:parasitology; D014709:Vero Cells
chemical_list: D001549:Benzamides; D014344:Trypanocidal Agents