title: Nitrotriazole-based acetamides and propanamides with broad spectrum antitrypanosomal activity.
abstract: 3-Nitro-1H-1,2,4-triazole-based acetamides bearing a biphenyl- or a phenoxyphenyl moiety have shown remarkable antichagasic activity both in vitro and in an acute murine model, as well as substantial in vitro antileishmanial activity but lacked activity against human African trypanosomiasis. We have shown now that by inserting a methylene group in the linkage to obtain the corresponding propanamides, both antichagasic and in particular anti-human African trypanosomiasis potency was increased. Therefore, IC50 values at low nM concentrations against both T. cruzi and T. b. rhodesiense, along with huge selectivity indices were obtained. Although several propanamides were active against Leishmania donovani, they were slightly less potent than their corresponding acetamides. There was a good correlation between lipophilicity (clogP value) and trypanocidal activity, for all new compounds. Type I nitroreductase, an enzyme absent from the human host, played a role in the activation of the new compounds, which may function as prodrugs. Antichagasic activity in vivo was also demonstrated with representative propanamides.
authors.affiliation: NorthShore University HealthSystem, Evanston, IL, United States. Electronic address: mvpapadopoulou@gmail.com.
authors.forename: Maria V
authors.initials: MV
authors.lastname: Papadopoulou
authors.affiliation: NorthShore University HealthSystem, Evanston, IL, United States.
authors.forename: William D
authors.initials: WD
authors.lastname: Bloomer
authors.affiliation: Oakton Community College, Des Plaines, IL, United States.
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: Shane R
authors.initials: SR
authors.lastname: Wilkinson
authors.affiliation: School of Biological & Chemical Sciences, Queen Mary University of London, London, UK.
authors.forename: Joanna
authors.initials: J
authors.lastname: Szular
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: D000081:Acetamides / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D051379:Mice; D009601:Nitroreductases / Q000378:metabolism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000502:physiology; D014353:Trypanosomiasis, African / Q000188:drug therapy / Q000378:metabolism
chemical_list: D000081:Acetamides; D014230:Triazoles; D014344:Trypanocidal Agents; C029492:aromatic NADH-dependent nitroreductase; D009601:Nitroreductases
keywords: Chagas disease; HAT disease; Leishmania; Nitrotriazoles; Type I nitroreductase