title: Novel nitro(triazole/imidazole)-based heteroarylamides/sulfonamides as potential antitrypanosomal agents.
abstract: We have previously shown that 3-nitro-1H-1,2,4-triazole-based arylamides and arylsulfonamides demonstrate significant activity in vitro against Trypanosoma cruzi, the causative parasite of Chagas disease. More importantly, several such analogs displayed significant antichagasic activity in vivo, superior to that of benznidazole, the current clinical standard. We now report the synthesis and in vitro evaluation of a small series of novel nitro(triazole/imidazole)-based heteroarylamides/sulfonamides (including 3-nitrotriazole-, 2- and 4-nitroimidazole-based compounds) as potential antitrypanosomal agents. All nitrotriazoles displayed significant growth inhibitory properties against T. cruzi with the most potent generating IC50 values of <1 μM and up to >1400-fold selectivity toward the parasite. The 2-nitroimidazole-based derivatives were moderately active against T. cruzi and displayed selectivity <50, while the 4-nitroimidazoles were mostly inactive. Several 3-nitrotriazole-based analogs showed activity against Trypanosoma brucei rhodesiense but none of the tested compounds displayed activity toward Leishmania donovani. From the detailed SARs presented here, we identified the 3-nitrotriazole-based chlorinated thiophene/benzothiophene sulfonamides/amides as being the most active antichagasic compounds, displaying up to 14-fold higher potency against T. cruzi than the reference compound benznidazole.
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: 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: D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects / Q000469:parasitology; D002478:Cells, Cultured; D014355:Chagas Disease / Q000188:drug therapy / Q000469:parasitology; D005434:Flow Cytometry; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D066298:In Vitro Techniques; D007893:Leishmania donovani / Q000187:drug effects*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000469:parasitology; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects / Q000469:parasitology; D015539:Platelet Activation / Q000187:drug effects; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D014230:Triazoles / Q000737:chemistry*; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D000577:Amides; D006571:Heterocyclic Compounds; D007093:Imidazoles; D013449:Sulfonamides; D014230:Triazoles; D014344:Trypanocidal Agents; C045575:1,2,4-triazole
keywords: Antitrypanosomal agents; Chagas disease; Heteroarylamides; Heteroarylsulfonamides; Nitroimidazoles; Nitrotriazoles