Exploring the potential activity spectrum of two 5-nitroindazolinone prototypes on different Trypanosoma cruzi strains

Abstract

In the present study, the potential activity of two 5-nitroindazole derivatives previously proposed as suitable antichagasic prototypes was further evaluated on diverse Trypanosoma cruzi strains belonging to two discrete typing units (DTUs) frequently associated with human infection (i.e. DTUs TcII and TcVI). The trypanocidal profile that both 2-benzyl-1-propyl (22) and 2-benzyl-1-butyl (24) derivatives achieved on Tulahuen amastigotes (IC 50 = 3·56 ± 0·99 and 6·31 ± 1·04 µM, respectively) correlates with that of formerly obtained on CL Brener, corroborating an outstanding activity on DTU TcVI parasites. Moreover, a sequential screening on extracellular and intracellular stages of T. cruzi Y (DTU TcII) demonstrated also the effectiveness of 22 and 24 over this strain on a similar range of activity (IC 50 epimastigotes = 3·55 ± 0·47 and 7·92 ± 1·63 µM, IC 50 amastigotes = 2·80 ± 0·46 and 9·02 ± 5·26 µM, respectively). These results, supported by a lack of toxicity registered over either L929 fibroblasts or primary cultures of cardiomyocytes, confirm that 5-nitroindazolinones 22 and 24 display great selectivity on both drug-sensitive (CL and Tulahuen) and drug-moderately resistant (Y) T. cruzi strains, and therefore, represent an important outcome in the research of Chagas disease chemotherapy.

Antichagasic, Leishmanicidal, and Trichomonacidal Activity of 2‐Benzyl‐5‐nitroindazole‐Derived Amines

“…The trypanocidal properties of 1‐substituted 2‐benzylindazolin‐3‐ones (series A ) previously described were confirmed in the current work. Among compounds of this series, primary amines ( 16 , 17 ) were the most active compounds, followed by secondary amines ( 19 ).…”

“…Within the area of new potential antichagasic drugs, we recently described the synthesis and activity of many 5‐nitroindazole derivatives. In direct relationship to the current work, we highlighted interesting results found for several 1,2‐disubstituted indazolin‐3‐ones . The trypanocidal properties of some 3‐alkoxy‐1‐alkylindazoles were also reported …”

“…Thus, these compounds fulfill the requirements for activities and SI values against amastigotes of a TcVI strain needed to be considered good starting points for the development of antichagasic hit compounds (IC 50 <5 μ m or ≤10 μ m , and SI>10) . Furthermore, based on the involvement of cardiac cells in the pathology of chronic Chagas disease, compounds 11 , 17 , 19 , and 21 were also assayed against these target cells; the absence of in vitro toxicity of these indazolinones (LC 50 >100 μ m , Table ) supports their specific trypanocidal activity.…”

“…Amastigote susceptibility assays : The activity toward intracellular amastigotes was studied by infecting either L929 murine fibroblasts (CCL‐1 line, ATCC) with culture‐derived trypomastigotes (CL‐B5 and Tulahuen strains, both stably transfected with the E. coli β‐galactosidase gene) or murine cardiac cells with bloodstream trypomastigotes (Y strain), as reported previously …”

Activity of 2-benzyl-1-(2-hydroxyethyl)-5-nitroindazolin-3-one on Trypanosoma cruzi Bloodstream Trypomastigotes (Y strain): In Vitro and In Vivo Studies

“…In this context, our group has proposed 5-nitroindazole derivatives as antichagasic prototypes, according to their activity in vitro and in vivo [1][2][3][4][5]. The lack of cytotoxicity and outstanding activity on the replicative forms of Trypanosoma cruzi (i.e., epimastigotes and intracellular amastigotes) previously shown by 2-benzyl-1-(2-hydroxyethyl)-5-nitroindazolin-3-one [5], encouraged assaying this compound in vitro on bloodstream trypomastigotes of Y strain (DTU TcII) and then, moved it to murine models of toxicity and infection.…”