title: Novel 3-nitro-1H-1,2,4-triazole-based amides and sulfonamides as potential antitrypanosomal agents.
abstract: A series of novel 3-nitro-1H-1,2,4-triazole-based (and in some cases 2-nitro-1H-imidazole-based) amides and sulfonamides were characterized for their in vitro antitrypanosomal and antileishmanial activities as well as mammalian toxicity. Out of 36 compounds tested, 29 (mostly 3-nitro-1H-1,2,4-triazoles) displayed significant activity against  Trypanosoma cruzi  intracellular amastigotes (IC(50) ranging from 28 nM to 3.72 μM) without concomitant toxicity to L6 host cells (selectivity 66-2782). Twenty-three of these active compounds were more potent (up to 58-fold) than the reference drug benznidazole, tested in parallel. In addition, nine nitrotriazoles which were moderately active (0.5 μM ≤ IC(50) < 6.0 μM) against  Trypanosoma brucei rhodesiense  trypomastigotes were 5-31-fold more active against bloodstream-form  Trypanosoma brucei brucei  trypomastigotes engineered to overexpress reduced nicotinamide adenine dinucleotide dependent nitroreductase. Finally, three nitrotriazoles displayed a moderate activity against the axenic form of  Leishmania donovani . Therefore, 3-nitro-1H-1,2,4-triazole-based amides and sulfonamides are potent antitrypanosomal agents.
authors.affiliation: NorthShore University HealthSystem, Evanston, Illinois, United States. mpapadopoulou@northshore.org
authors.forename: Maria V
authors.initials: MV
authors.lastname: Papadopoulou
authors.forename: William D
authors.initials: WD
authors.lastname: Bloomer
authors.forename: Howard S
authors.initials: HS
authors.lastname: Rosenzweig
authors.forename: Eric
authors.initials: E
authors.lastname: Chatelain
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: Shane R
authors.initials: SR
authors.lastname: Wilkinson
authors.forename: Caroline
authors.initials: C
authors.lastname: McKenzie
authors.forename: Jean-Robert
authors.initials: JR
authors.lastname: Ioset
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D007893:Leishmania donovani / Q000187:drug effects; D009574:Nitro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009601:Nitroreductases / Q000378:metabolism; D021261:Parasitic Sensitivity Tests; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology; D014349:Trypanosoma cruzi / Q000187:drug effects
chemical_list: D000577:Amides; D009574:Nitro Compounds; D011355:Prodrugs; D013449:Sulfonamides; D014230:Triazoles; D014344:Trypanocidal Agents; C029492:aromatic NADH-dependent nitroreductase; D009601:Nitroreductases