Novel 3-nitro-1H-1,2,4-triazole-based aliphatic and aromatic amines as anti-chagasic agents.
A series of novel 2-nitro-1H-imidazole- and 3-nitro-1H-1,2,4-triazole-based aromatic and aliphatic amines were screened for antitrypanosomal activity and mammalian cytotoxicity by the Drugs for Neglected Diseases initiative (DNDi). Out of 42 compounds tested, 18 3-nitro-1,2,4-triazoles and one 2-nitroimidazole displayed significant growth inhibitory properties against  T. cruzi  amastigotes (IC(50) ranging from 40 nM to 1.97 μM), without concomitant toxicity toward the host cells (L6 cells), having selectivity indices (SI) 44-1320. Most (16) of these active compounds were up to 33.8-fold more potent than the reference drug benznidazole, tested in parallel. Five novel 3-nitro-1,2,4-triazoles were active against bloodstream-form (BSF)  T. b. rhodesiense  trypomastigotes (IC(50) at nM levels and SI 220-993). An NADH-dependent nitroreductase (TbNTR) plays a role in the antiparasitic activity because BSF  T. b. brucei  trypomastigotes with elevated TbNTR levels were hypersensitive to tested compounds. Therefore, a novel class of affordable 3-nitro-1,2,4-triazole-based compounds with antitrypanosomal activity has been identified.
NorthShore University HealthSystem, Department of Radiation Medicine, Evanston, Illinois 60201, United States. mpapadopoulou@northshore.org
Maria V
MV
Papadopoulou
Bernadette Bourdin
BB
Trunz
William D
WD
Bloomer
Caroline
C
McKenzie
Shane R
SR
Wilkinson
Chaiya
C
Prasittichai
Reto
R
Brun
Marcel
M
Kaiser
Els
E
Torreele
D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D014355:Chagas Disease / Q000188:drug therapy / Q000469:parasitology; D007893:Leishmania donovani / Q000187:drug effects; D051379:Mice; D009574:Nitro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021261:Parasitic Sensitivity Tests; D051381:Rats; D013329:Structure-Activity Relationship; 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; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects; D014349:Trypanosoma cruzi
D000588:Amines; D009574:Nitro Compounds; D014230:Triazoles; D014344:Trypanocidal Agents