Activity of n-benzenesulfonyl derivatives of heterocycles against Trypanosoma cruzi trypomastigotes

MIANA G; LO PRESTI MS; PAGLINI PA; MAZZIERI MR

Rosario

Congreso; 2º Reunión Internacional de Ciencias Farmacéuticas.; 2012

Introduction A chemical library of N-benzenesulfonyl derivatives of bioactive heterocycles (N-BSHet) was design and synthetized in our laboratories. It was submitted for antiparasitic and citotoxic high throughput screening (HTS) as well, rendering 10 (of 109) compounds with IC50 <10 µM against Trypanosoma cruzi (Tc) amastigotes (1,2). In addition, one of those derivative showed bactericidal and anti-Tc activity against epimastigotes and purified trypomastigotes (3,4). Because of some of the determinations of the HTS could be interpreted as a false negative result, we decided to explore another anti-Tc assay. Therefore, currently we are exploring the in vitro activity against bloodstream trypomastigotes of Tc, which is the most interesting form because it is the one responsible for the dissemination of the infection and the cause of Chagas disease. Simultaneously, we are carrying out virtual screening over different therapeutic and molecular targets related with biochemical routes of Tc in order to gather information to better select the prototypes.   Materials and methods The biologic assays of four N-BSHet derivatives were performed as described by Paglini et al. (5) with some modifications (blood of female mice and 15 days after infection). The blood containing Tc trypomastigotes (Tulahuen strain) was incubated with the N-BSHet in DMSO at different concentrations (µg/mL). Then, the number of motile forms of Tc was determined by optical microscopy (triplicate) at 0 and 40 minutes. Finally, the statistical analysis (paired test t) was performed by using InfoStat® software.   Results The method selected for the assays allowed to calculate the % of trypomastigotes reduction (Table 1) after incubating Tc bloodstream forms with 1, 2, 3 y 4 (Figure 1) at concentrations of 75 y 100 µg/mL, during 40 minutes. Benznidazol (BZN) was included as reference and positive assay. The N-BSHet assayed showed moderated in vitro activity against Tc (Tulahuen strain, trypomatigotes), being compound 3 the most active (only four times less than BZN).   Conclusions Some N-BSHet derivatives of the chemical library showed moderate antitripanosome activity against the infective form of Tc. From the present results, all of the studied compounds could be selected as hits. Therefore, we propose to continue with the synthesis of analogues of them and with the same screening.   Acknowledgments The authors acknowledge CONICET for the grant and the financial support of Secretary of Science and Technology (SECYT-UNC).   References. 1) Pagliero RJ, Lusvarghi S, Pierini AB, Brun R, Mazzieri MR. Design, synthesis and 3-D characterization of 1-benzenesulfonyl-1,2,3,4-tetrahydroquinolines as lead scaffold for antiparasitic drug. Lett. Drug. Discov. 2010, 7(6):461-70. 2) Pagliero RJ Pierini AB, Brun R, Mazzieri MR. Synthesis, stereoelectronic characterization and antiparasitic activity of new 1-benzenesulfonyl-2-methyl-1,2,3,4-tetrahydroquinolines. Bioorg. Med. Chem. 2010, 18, 142-50. 3) Hergert LY, Nieto M, Becerra MC, Albesa I, Mazzieri MR. Synthesis of N-Benzenesulfonylbenzotriazole Derivatives, and Evaluation of their Antimicrobial Activity. Lett. Drug  Des. Discov. 2008, 5, 313-318.