MAZZIERI MARIA ROSA
Congresos y reuniones científicas
Título:
ACTIVITY OF N-BENZENESULFONYL DERIVATIVES OF HETEROCYCLES AGAINST TRYPANOSOMA CRUZI TRYPOMASTIGOTES
Autor/es:
MIANA, G; LO PRESTI, MS; PAGLINI-OLIVA, P; MAZZIERI, MR
Lugar:
Rosario, Santa Fé
Reunión:
Congreso; 2da Reunión Internacional de Ciencias Farmacéuticas (RICiFa); 2012
Institución organizadora:
Fac. de Ciencias Químicas, UNC
Resumen:
ACTIVITY OF N-BENZENESULFONYL DERIVATIVES OF HETEROCYCLES AGAINST TRYPANOSOMA CRUZI TRYPOMASTIGOTES
Miana GEa, Lo Presti MSb, Paglini-OlivaPb, Mazzieri MRa
a Departamento de Farmacia, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba
Haya de la Torre esq. Medina Allende, Córdoba, CP: 5000
b Cátedra de Física Biomédica, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba
Santa Rosa 1085, Córdoba, CP: 5000
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.
4) Becerra MC, Guiñazú N, Hergert LY, Pellegrini A, Mazzieri MR, Gea S, Albesa I. In vitro activity of Nbenzenesulfonylbenzotriazole
on Trypanosoma cruzi epimastigote and trypomastigote forms. Exp Parasitol.
2012, 131, 57-62.
5) Paglini-Oliva P, Fernandez AR, Fretes R, Peslman A. Structural, ultrastructural studies and evolution of
Trypanosoma cruzi-infected mice treated with thioridazine. Exp. Mol. Pathol. 1998, 65, (2), 78-86.
Table 1 - Percent of trypomastigotes reduction (40 minutes).
Compound
Concentration (μg/mL.)
Trypomastigotes reduction (%)
1 100 34,2
2 100 52,0
3 75 55,3
3 100 66,0
4 75 48,0
4 100 37,4
BZN 25 66,1
Figure 1. N-BSHet derivatives studied over Tc trypomastigote.
Corresponding author. Tel. y Fax +54 351 5353865; e-mail: mrmazzie@fcq.unc.edu.ar
Miana GEa, Lo Presti MSb, Paglini-OlivaPb, Mazzieri MRa
a Departamento de Farmacia, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba
Haya de la Torre esq. Medina Allende, Córdoba, CP: 5000
b Cátedra de Física Biomédica, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba
Santa Rosa 1085, Córdoba, CP: 5000
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.
4) Becerra MC, Guiñazú N, Hergert LY, Pellegrini A, Mazzieri MR, Gea S, Albesa I. In vitro activity of Nbenzenesulfonylbenzotriazole
on Trypanosoma cruzi epimastigote and trypomastigote forms. Exp Parasitol.
2012, 131, 57-62.
5) Paglini-Oliva P, Fernandez AR, Fretes R, Peslman A. Structural, ultrastructural studies and evolution of
Trypanosoma cruzi-infected mice treated with thioridazine. Exp. Mol. Pathol. 1998, 65, (2), 78-86.
Table 1 - Percent of trypomastigotes reduction (40 minutes).
Compound
Concentration (μg/mL.)
Trypomastigotes reduction (%)
1 100 34,2
2 100 52,0
3 75 55,3
3 100 66,0
4 75 48,0
4 100 37,4
BZN 25 66,1
Figure 1. N-BSHet derivatives studied over Tc trypomastigote.
Corresponding author. Tel. y Fax +54 351 5353865; e-mail: mrmazzie@fcq.unc.edu.ar
