title: 3-Nitrotriazole-based piperazides as potent antitrypanosomal agents.
abstract: Novel linear 3-nitro-1H-1,2,4-triazole-based piperazides were synthesized and evaluated as antitrypanosomal agents. In addition, some bisarylpiperazine-ethanones which were formed as by-products were also screened for antiparasitic activity. Most 3-nitrotriazole-based derivatives were potent and selective against Trypanosoma cruzi parasites, but only one displayed these desired properties against Trypanosoma brucei rhodesiense. Moreover, two 3-nitrotriazole-based chlorophenylpiperazides were moderately and selectively active against Leishmania donovani. Although the bisarylpiperazine-ethanones were active or moderately active against T. cruzi, none of them demonstrated an acceptable selectivity. In general, 3-nitrotriazole-based piperazides were less toxic to host L6 cells than the previously evaluated 3-nitrotriazole-based piperazines and seven of 13 were 1.54- to 31.2-fold more potent antichagasic agents than the reference drug benznidazole. Selected compounds showed good ADMET characteristics. One potent in vitro antichagasic compound (3) was tested in an acute murine model and demonstrated antichagasic activity after a 10-day treatment of 15 mg/kg/day. However, neither compound 3 nor benznidazole showed a statistically significant P value compared to control due to high variability in parasite burden among the untreated animals. Working as prodrugs, 3-nitrotriazole-based piperazides were excellent substrates of trypanosomal type I nitroreductases and constitute a novel class of potentially effective and more affordable antitrypanosomal agents.
authors.affiliation: NorthShore University HealthSystem, Evanston, IL, USA. Electronic address: mpapadopoulou@northshore.org.
authors.forename: Maria V
authors.initials: MV
authors.lastname: Papadopoulou
authors.affiliation: NorthShore University HealthSystem, Evanston, IL, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Bloomer
authors.affiliation: Oakton Community College, Des Plaines, IL, USA.
authors.forename: Howard S
authors.initials: HS
authors.lastname: Rosenzweig
authors.affiliation: School of Biological & Chemical Sciences, Queen Mary University of London, London, UK.
authors.forename: Ivan P
authors.initials: IP
authors.lastname: O'Shea
authors.affiliation: School of Biological & Chemical Sciences, Queen Mary University of London, London, UK.
authors.forename: Shane R
authors.initials: SR
authors.lastname: Wilkinson
authors.affiliation: Swiss Tropical and Public Health Institute, Parasite Chemotherapy, Basel, Switzerland; University of Basel, Basel, Switzerland.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
mesh_terms: D000818:Animals; D002460:Cell Line; D014355:Chagas Disease / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects*; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D010879:Piperazines; D014230:Triazoles; D014344:Trypanocidal Agents
keywords: Chagas disease; Leishmanicidal; Nitrotriazoles; Piperazides; Trypanocidal