Discovery of potent nitrotriazole-based antitrypanosomal agents: In vitro and in vivo evaluation.
3-Nitro-1H-1,2,4-triazole- and 2-nitro-1H-imidazole-based amides with an aryloxy-phenyl core were synthesized and evaluated as antitrypanosomal agents. All 3-nitrotriazole-based derivatives were extremely potent anti-Trypanosoma cruzi agents at sub nM concentrations and exhibited a high degree of selectivity for the parasite. The 2-nitroimidazole analogs were only moderately active against T. cruzi amastigotes and exhibited low selectivity. Both types of compound were active against Leishmania donovani axenic amastigotes with excellent selectivity for the parasite, whereas three 2-nitroimidazole-based analogs were also moderately active against infected macrophages. However, no compound demonstrated selective activity against Trypanosoma brucei rhodesiense. The most potent in vitro anti-T. cruzi compounds were tested in an acute murine model and reduced the parasites to an undetectable level after five days of treatment at 13 mg/kg/day. Such compounds are potential inhibitors of T. cruzi CYP51 and, being excellent substrates for the type I nitroreductase (NTR) which is specific to trypanosomatids, work as prodrugs and constitute a new generation of effective and more affordable antitrypanosomal agents.
NorthShore University HealthSystem, Department of Radiation Medicine, 2650 Ridge Ave., Evanston, IL 60201, USA. Electronic address: mpapadopoulou@northshore.org.
Maria V
MV
Papadopoulou
NorthShore University HealthSystem, Department of Radiation Medicine, 2650 Ridge Ave., Evanston, IL 60201, USA.
William D
WD
Bloomer
Oakton Community College, Des Plaines, IL, USA.
Howard S
HS
Rosenzweig
School of Biological & Chemical Sciences, Queen Mary University of London, London, UK.
Ivan P
IP
O'Shea
School of Biological & Chemical Sciences, Queen Mary University of London, London, UK.
Shane R
SR
Wilkinson
Swiss Tropical and Public Health Institute, Parasite Chemotherapy, Basel, Switzerland; University of Basel, Basel, Switzerland.
Marcel
M
Kaiser
Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland.
Eric
E
Chatelain
Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland.
Jean-Robert
JR
Ioset
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D014355:Chagas Disease / Q000188:drug therapy; D004195:Disease Models, Animal; D007893:Leishmania donovani / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009601:Nitroreductases / Q000737:chemistry / Q000378:metabolism; D021261:Parasitic Sensitivity Tests; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D058886:Sterol 14-Demethylase / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology
D011355:Prodrugs; D015800:Protozoan Proteins; D014230:Triazoles; D014344:Trypanocidal Agents; C029492:aromatic NADH-dependent nitroreductase; D058886:Sterol 14-Demethylase; D009601:Nitroreductases
Antitrypanosomal agents; Chagas disease; L. donovani; Nitroimidazoles; Nitrotriazoles; Type I nitroreductase