The Experts below are selected from a list of 7662 Experts worldwide ranked by ideXlab platform
Frederick Cohen - One of the best experts on this subject based on the ideXlab platform.
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synthesis and structure activity relationship study of potent Trypanocidal thio semicarbazone inhibitors of the trypanosomal cysteine protease cruzain
Journal of Medicinal Chemistry, 2002Co-Authors: Xiaohui Du, Conor R Caffrey, Tod P Holler, James H Mckerrow, Elizabeth Hansell, Patricia S. Doyle, Frederick CohenAbstract:American trypanosomiasis, or Chagas' disease, is the leading cause of heart disease in Latin America. Currently there is an urgent need to develop antitrypanosomal therapy due to the toxicity of existing agents and emerging drug resistance. A novel series of potent thio semicarbazone small-molecule inhibitors of the Trypanosoma cruzi cysteine protease cruzain have been identified. Some of these inhibitors have been shown to be Trypanocidal. We initially discovered that 3‘-bromopropiophenone thio semicarbazone (1i) inhibited cruzain and could cure mammalian cell cultures infected with T. cruzi. 3‘-Bromopropiophenone thio semicarbazone showed no toxicity for mammalian cells at concentrations that were Trypanocidal. Following this lead, more than 100 compounds were designed and synthesized. A specific structure−activity relationship (SAR) was established, and many potent analogues with IC50 values in the low nanomolar range were identified. Eight additional analogues were Trypanocidal in a cell culture assay...
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synthesis and structure activity relationship study of potent Trypanocidal thio semicarbazone inhibitors of the trypanosomal cysteine protease cruzain
Journal of Medicinal Chemistry, 2002Co-Authors: Chun Guo, Conor R Caffrey, Tod P Holler, James H Mckerrow, Elizabeth Hansell, Patricia S. Doyle, Frederick CohenAbstract:American trypanosomiasis, or Chagas' disease, is the leading cause of heart disease in Latin America. Currently there is an urgent need to develop antitrypanosomal therapy due to the toxicity of existing agents and emerging drug resistance. A novel series of potent thio semicarbazone small-molecule inhibitors of the Trypanosoma cruzi cysteine protease cruzain have been identified. Some of these inhibitors have been shown to be Trypanocidal. We initially discovered that 3'-bromopropiophenone thio semicarbazone (1i) inhibited cruzain and could cure mammalian cell cultures infected with T. cruzi. 3'-Bromopropiophenone thio semicarbazone showed no toxicity for mammalian cells at concentrations that were Trypanocidal. Following this lead, more than 100 compounds were designed and synthesized. A specific structure-activity relationship (SAR) was established, and many potent analogues with IC(50) values in the low nanomolar range were identified. Eight additional analogues were Trypanocidal in a cell culture assay, and this indicates that aryl thio semicarbazone is a productive scaffold for killing the parasites. Kinetic studies show that these are time-dependent inhibitors. Molecular modeling studies of the enzyme-inhibitor complex have led to a proposed mechanism of interaction as well as insight into the SAR of the thio semicarbazone series. The nonpeptide nature of this series, small size, and extremely low cost of production suggest this is a promising direction for the development of new antitrypanosome chemotherapy.
James H Mckerrow - One of the best experts on this subject based on the ideXlab platform.
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aziridine 2 3 dicarboxylate inhibitors targeting the major cysteine protease of trypanosoma brucei as lead Trypanocidal agents
Bioorganic & Medicinal Chemistry Letters, 2006Co-Authors: Radim Vicik, Conor R Caffrey, James H Mckerrow, Elizabeth Hansell, Verena Hoerr, Melanie Glaser, Martina Schultheis, Ulrike Holzgrabe, Alicia PontesucreAbstract:Abstract The protozoan parasite Trypanosoma brucei causes Human African trypanosomiasis, which is fatal if left untreated. Due to the toxicity of currently used drugs and emerging drug resistance, there is an urgent need for novel therapies. The major trypanosome papain-like cysteine protease expressed by the parasite (e.g., rhodesain in T. b. rhodesiense) is considered an important target for the development of new Trypanocidal drugs. Series of aziridine-2,3-dicarboxylate-based cysteine protease inhibitors have been tested, most of them inhibiting rhodesain in the low micromolar range. Among these, only dibenzyl aziridine-2,3-dicarboxylates display Trypanocidal activity being equipotent to the drug eflornithine. The Leu-Pro-containing aziridinyl tripeptides 13a–f are the most promising as they are not cytotoxic to macrophages up to concentrations of 125 μM.
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discovery of Trypanocidal compounds by whole cell hts of trypanosoma brucei
Chemical Biology & Drug Design, 2006Co-Authors: Zachary B Mackey, Elizabeth Hansell, Arthur M Baca, Jeremy P Mallari, Beth Apsel, Anang Shelat, Peter K Chiang, Brian Wolff, Janice Williams, James H MckerrowAbstract:Chemotherapy against human African trypanosomiasis relies on four drugs that cause frequent and occasionally severe side-effects. Because human African trypanosomiasis is a disease of poor people in Africa, the traditional market-driven pathways to drug development are not available. One potentially rapid and cost-effective approach to identifying and developing new Trypanocidal drugs would be high throughput-screening of existing drugs already approved for other uses, as well as clinical candidates in late development. We have developed an ATP-bioluminescence assay that could be used to rapidly and efficiently screen compound libraries against trypanosomes in a high throughput-screening format to validate this notion. We screened a collection of 2160 FDA-approved drugs, bioactive compounds and natural products to identify hits that were cytotoxic to cultured Trypanosoma brucei at a concentration of 1 μm or less. This meant that any hit identified would be effective at a concentration readily achievable by standard drug dosing in humans. From the screen, 35 hits from seven different drug categories were identified. These included the two approved Trypanocidal drugs, suramin and pentamidine, several other drugs suspected but never validated as Trypanocidal, and 17 novel Trypanocidal drugs.
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synthesis and structure activity relationship study of potent Trypanocidal thio semicarbazone inhibitors of the trypanosomal cysteine protease cruzain
Journal of Medicinal Chemistry, 2002Co-Authors: Xiaohui Du, Conor R Caffrey, Tod P Holler, James H Mckerrow, Elizabeth Hansell, Patricia S. Doyle, Frederick CohenAbstract:American trypanosomiasis, or Chagas' disease, is the leading cause of heart disease in Latin America. Currently there is an urgent need to develop antitrypanosomal therapy due to the toxicity of existing agents and emerging drug resistance. A novel series of potent thio semicarbazone small-molecule inhibitors of the Trypanosoma cruzi cysteine protease cruzain have been identified. Some of these inhibitors have been shown to be Trypanocidal. We initially discovered that 3‘-bromopropiophenone thio semicarbazone (1i) inhibited cruzain and could cure mammalian cell cultures infected with T. cruzi. 3‘-Bromopropiophenone thio semicarbazone showed no toxicity for mammalian cells at concentrations that were Trypanocidal. Following this lead, more than 100 compounds were designed and synthesized. A specific structure−activity relationship (SAR) was established, and many potent analogues with IC50 values in the low nanomolar range were identified. Eight additional analogues were Trypanocidal in a cell culture assay...
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synthesis and structure activity relationship study of potent Trypanocidal thio semicarbazone inhibitors of the trypanosomal cysteine protease cruzain
Journal of Medicinal Chemistry, 2002Co-Authors: Chun Guo, Conor R Caffrey, Tod P Holler, James H Mckerrow, Elizabeth Hansell, Patricia S. Doyle, Frederick CohenAbstract:American trypanosomiasis, or Chagas' disease, is the leading cause of heart disease in Latin America. Currently there is an urgent need to develop antitrypanosomal therapy due to the toxicity of existing agents and emerging drug resistance. A novel series of potent thio semicarbazone small-molecule inhibitors of the Trypanosoma cruzi cysteine protease cruzain have been identified. Some of these inhibitors have been shown to be Trypanocidal. We initially discovered that 3'-bromopropiophenone thio semicarbazone (1i) inhibited cruzain and could cure mammalian cell cultures infected with T. cruzi. 3'-Bromopropiophenone thio semicarbazone showed no toxicity for mammalian cells at concentrations that were Trypanocidal. Following this lead, more than 100 compounds were designed and synthesized. A specific structure-activity relationship (SAR) was established, and many potent analogues with IC(50) values in the low nanomolar range were identified. Eight additional analogues were Trypanocidal in a cell culture assay, and this indicates that aryl thio semicarbazone is a productive scaffold for killing the parasites. Kinetic studies show that these are time-dependent inhibitors. Molecular modeling studies of the enzyme-inhibitor complex have led to a proposed mechanism of interaction as well as insight into the SAR of the thio semicarbazone series. The nonpeptide nature of this series, small size, and extremely low cost of production suggest this is a promising direction for the development of new antitrypanosome chemotherapy.
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Cysteine proteinase inhibitors kill cultured bloodstream forms of Trypanosoma brucei brucei.
Experimental parasitology, 1999Co-Authors: Linda Troeberg, James T. Palmer, John D. Lonsdale-eccles, Rory E. Morty, Robert N. Pike, James H Mckerrow, Theresa H.t. CoetzerAbstract:Trypanosoma brucei brucei is a causative agent of bovine trypanosomiasis (nagana), a disease of considerable economic significance in much of Africa. Here we report investigations on the effects of various irreversible cysteine proteinase inhibitors, including vinyl sulfones (VS), peptidyl chloromethylketones (CMK), diazomethylketones, and fluoromethyl ketones, on the major lysosomal cysteine proteinase (trypanopain-Tb) of T. b. brucei and on in vitro-cultured bloodstream forms of the parasite. Many of the tested inhibitors were Trypanocidal at low micromolar concentrations. Methylpiperazine urea-Phe-homoPhe-VS was the most effective Trypanocidal agent, killing 50% of test populations at a work ing concentration of 0.11 microM, while carbobenzoxy-Phe-Phe-CMK was the most Trypanocidal of the methylketones with an IC50 of 3.6 microM. Labelling of live and lysed T. b. brucei with biotinylated inhibitor derivatives suggests that trypanopain-Tb is the likely intracellular target for these inhibitors. Kinetic analysis of the inhibition of purified trypanopain-Tb by the inhibitors showed that most had kass values in the 10(6) M-1 s-1 range. We conclude that cysteine proteinase inhibitors have potential as Trypanocidal agents and that a major target of these compounds is the lysosomal enzyme trypanopain-Tb.
Elizabeth Hansell - One of the best experts on this subject based on the ideXlab platform.
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aziridine 2 3 dicarboxylate inhibitors targeting the major cysteine protease of trypanosoma brucei as lead Trypanocidal agents
Bioorganic & Medicinal Chemistry Letters, 2006Co-Authors: Radim Vicik, Conor R Caffrey, James H Mckerrow, Elizabeth Hansell, Verena Hoerr, Melanie Glaser, Martina Schultheis, Ulrike Holzgrabe, Alicia PontesucreAbstract:Abstract The protozoan parasite Trypanosoma brucei causes Human African trypanosomiasis, which is fatal if left untreated. Due to the toxicity of currently used drugs and emerging drug resistance, there is an urgent need for novel therapies. The major trypanosome papain-like cysteine protease expressed by the parasite (e.g., rhodesain in T. b. rhodesiense) is considered an important target for the development of new Trypanocidal drugs. Series of aziridine-2,3-dicarboxylate-based cysteine protease inhibitors have been tested, most of them inhibiting rhodesain in the low micromolar range. Among these, only dibenzyl aziridine-2,3-dicarboxylates display Trypanocidal activity being equipotent to the drug eflornithine. The Leu-Pro-containing aziridinyl tripeptides 13a–f are the most promising as they are not cytotoxic to macrophages up to concentrations of 125 μM.
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discovery of Trypanocidal compounds by whole cell hts of trypanosoma brucei
Chemical Biology & Drug Design, 2006Co-Authors: Zachary B Mackey, Elizabeth Hansell, Arthur M Baca, Jeremy P Mallari, Beth Apsel, Anang Shelat, Peter K Chiang, Brian Wolff, Janice Williams, James H MckerrowAbstract:Chemotherapy against human African trypanosomiasis relies on four drugs that cause frequent and occasionally severe side-effects. Because human African trypanosomiasis is a disease of poor people in Africa, the traditional market-driven pathways to drug development are not available. One potentially rapid and cost-effective approach to identifying and developing new Trypanocidal drugs would be high throughput-screening of existing drugs already approved for other uses, as well as clinical candidates in late development. We have developed an ATP-bioluminescence assay that could be used to rapidly and efficiently screen compound libraries against trypanosomes in a high throughput-screening format to validate this notion. We screened a collection of 2160 FDA-approved drugs, bioactive compounds and natural products to identify hits that were cytotoxic to cultured Trypanosoma brucei at a concentration of 1 μm or less. This meant that any hit identified would be effective at a concentration readily achievable by standard drug dosing in humans. From the screen, 35 hits from seven different drug categories were identified. These included the two approved Trypanocidal drugs, suramin and pentamidine, several other drugs suspected but never validated as Trypanocidal, and 17 novel Trypanocidal drugs.
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synthesis and structure activity relationship study of potent Trypanocidal thio semicarbazone inhibitors of the trypanosomal cysteine protease cruzain
Journal of Medicinal Chemistry, 2002Co-Authors: Xiaohui Du, Conor R Caffrey, Tod P Holler, James H Mckerrow, Elizabeth Hansell, Patricia S. Doyle, Frederick CohenAbstract:American trypanosomiasis, or Chagas' disease, is the leading cause of heart disease in Latin America. Currently there is an urgent need to develop antitrypanosomal therapy due to the toxicity of existing agents and emerging drug resistance. A novel series of potent thio semicarbazone small-molecule inhibitors of the Trypanosoma cruzi cysteine protease cruzain have been identified. Some of these inhibitors have been shown to be Trypanocidal. We initially discovered that 3‘-bromopropiophenone thio semicarbazone (1i) inhibited cruzain and could cure mammalian cell cultures infected with T. cruzi. 3‘-Bromopropiophenone thio semicarbazone showed no toxicity for mammalian cells at concentrations that were Trypanocidal. Following this lead, more than 100 compounds were designed and synthesized. A specific structure−activity relationship (SAR) was established, and many potent analogues with IC50 values in the low nanomolar range were identified. Eight additional analogues were Trypanocidal in a cell culture assay...
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synthesis and structure activity relationship study of potent Trypanocidal thio semicarbazone inhibitors of the trypanosomal cysteine protease cruzain
Journal of Medicinal Chemistry, 2002Co-Authors: Chun Guo, Conor R Caffrey, Tod P Holler, James H Mckerrow, Elizabeth Hansell, Patricia S. Doyle, Frederick CohenAbstract:American trypanosomiasis, or Chagas' disease, is the leading cause of heart disease in Latin America. Currently there is an urgent need to develop antitrypanosomal therapy due to the toxicity of existing agents and emerging drug resistance. A novel series of potent thio semicarbazone small-molecule inhibitors of the Trypanosoma cruzi cysteine protease cruzain have been identified. Some of these inhibitors have been shown to be Trypanocidal. We initially discovered that 3'-bromopropiophenone thio semicarbazone (1i) inhibited cruzain and could cure mammalian cell cultures infected with T. cruzi. 3'-Bromopropiophenone thio semicarbazone showed no toxicity for mammalian cells at concentrations that were Trypanocidal. Following this lead, more than 100 compounds were designed and synthesized. A specific structure-activity relationship (SAR) was established, and many potent analogues with IC(50) values in the low nanomolar range were identified. Eight additional analogues were Trypanocidal in a cell culture assay, and this indicates that aryl thio semicarbazone is a productive scaffold for killing the parasites. Kinetic studies show that these are time-dependent inhibitors. Molecular modeling studies of the enzyme-inhibitor complex have led to a proposed mechanism of interaction as well as insight into the SAR of the thio semicarbazone series. The nonpeptide nature of this series, small size, and extremely low cost of production suggest this is a promising direction for the development of new antitrypanosome chemotherapy.
Conor R Caffrey - One of the best experts on this subject based on the ideXlab platform.
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aziridine 2 3 dicarboxylate inhibitors targeting the major cysteine protease of trypanosoma brucei as lead Trypanocidal agents
Bioorganic & Medicinal Chemistry Letters, 2006Co-Authors: Radim Vicik, Conor R Caffrey, James H Mckerrow, Elizabeth Hansell, Verena Hoerr, Melanie Glaser, Martina Schultheis, Ulrike Holzgrabe, Alicia PontesucreAbstract:Abstract The protozoan parasite Trypanosoma brucei causes Human African trypanosomiasis, which is fatal if left untreated. Due to the toxicity of currently used drugs and emerging drug resistance, there is an urgent need for novel therapies. The major trypanosome papain-like cysteine protease expressed by the parasite (e.g., rhodesain in T. b. rhodesiense) is considered an important target for the development of new Trypanocidal drugs. Series of aziridine-2,3-dicarboxylate-based cysteine protease inhibitors have been tested, most of them inhibiting rhodesain in the low micromolar range. Among these, only dibenzyl aziridine-2,3-dicarboxylates display Trypanocidal activity being equipotent to the drug eflornithine. The Leu-Pro-containing aziridinyl tripeptides 13a–f are the most promising as they are not cytotoxic to macrophages up to concentrations of 125 μM.
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synthesis and structure activity relationship study of potent Trypanocidal thio semicarbazone inhibitors of the trypanosomal cysteine protease cruzain
Journal of Medicinal Chemistry, 2002Co-Authors: Xiaohui Du, Conor R Caffrey, Tod P Holler, James H Mckerrow, Elizabeth Hansell, Patricia S. Doyle, Frederick CohenAbstract:American trypanosomiasis, or Chagas' disease, is the leading cause of heart disease in Latin America. Currently there is an urgent need to develop antitrypanosomal therapy due to the toxicity of existing agents and emerging drug resistance. A novel series of potent thio semicarbazone small-molecule inhibitors of the Trypanosoma cruzi cysteine protease cruzain have been identified. Some of these inhibitors have been shown to be Trypanocidal. We initially discovered that 3‘-bromopropiophenone thio semicarbazone (1i) inhibited cruzain and could cure mammalian cell cultures infected with T. cruzi. 3‘-Bromopropiophenone thio semicarbazone showed no toxicity for mammalian cells at concentrations that were Trypanocidal. Following this lead, more than 100 compounds were designed and synthesized. A specific structure−activity relationship (SAR) was established, and many potent analogues with IC50 values in the low nanomolar range were identified. Eight additional analogues were Trypanocidal in a cell culture assay...
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synthesis and structure activity relationship study of potent Trypanocidal thio semicarbazone inhibitors of the trypanosomal cysteine protease cruzain
Journal of Medicinal Chemistry, 2002Co-Authors: Chun Guo, Conor R Caffrey, Tod P Holler, James H Mckerrow, Elizabeth Hansell, Patricia S. Doyle, Frederick CohenAbstract:American trypanosomiasis, or Chagas' disease, is the leading cause of heart disease in Latin America. Currently there is an urgent need to develop antitrypanosomal therapy due to the toxicity of existing agents and emerging drug resistance. A novel series of potent thio semicarbazone small-molecule inhibitors of the Trypanosoma cruzi cysteine protease cruzain have been identified. Some of these inhibitors have been shown to be Trypanocidal. We initially discovered that 3'-bromopropiophenone thio semicarbazone (1i) inhibited cruzain and could cure mammalian cell cultures infected with T. cruzi. 3'-Bromopropiophenone thio semicarbazone showed no toxicity for mammalian cells at concentrations that were Trypanocidal. Following this lead, more than 100 compounds were designed and synthesized. A specific structure-activity relationship (SAR) was established, and many potent analogues with IC(50) values in the low nanomolar range were identified. Eight additional analogues were Trypanocidal in a cell culture assay, and this indicates that aryl thio semicarbazone is a productive scaffold for killing the parasites. Kinetic studies show that these are time-dependent inhibitors. Molecular modeling studies of the enzyme-inhibitor complex have led to a proposed mechanism of interaction as well as insight into the SAR of the thio semicarbazone series. The nonpeptide nature of this series, small size, and extremely low cost of production suggest this is a promising direction for the development of new antitrypanosome chemotherapy.
Maria Helena Sarragiotto - One of the best experts on this subject based on the ideXlab platform.
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in vitro and in vivo Trypanocidal synergistic activity of n butyl 1 4 dimethylamino phenyl 1 2 3 4 tetrahydro β carboline 3 carboxamide associated with benznidazole
Antimicrobial Agents and Chemotherapy, 2012Co-Authors: Rodrigo Hinojosa Valdez, Edilson Nobuyoshi Kaneshima, Lilian Tatiani Dusman Tonin, Tânia Uedanakamura, Sueli De Oliveira Silva, Benedito Prado Dias Filho, Sueli Fumie Yamadaogatta, Lucy Megumi Yamauchi, Maria Helena SarragiottoAbstract:American trypanosomiasis, or Chagas' disease, is caused by Trypanosoma cruzi and affects around 15 million people throughout the American continent. The available treatment is based on two nitroheterocyclic drugs, nifurtimox and benznidazole, both only partially effective and toxic. In this context, new drugs must be found. In our previous work, the tetrahydro-β-carboline compound N-butyl-1-(4-dimethylamino)phenyl-1,2,3,4-tetrahydro-β-carboline-3-carboxamide, named C4, showed a potent in vitro Trypanocidal effect. The goal of this study was to evaluate the in vitro and in vivo Trypanocidal effects of the compound C4 associated with other drugs (benznidazole, ketoconazole, and amphotericin B). For this, we used the checkerboard technique to analyze the effect of combinations of C4 reference drugs. C4 was assayed in a murine model alone as well as in association with benznidazole. We also evaluated the parasitemia, mortality, weight, and presence of amastigote nests in cardiac tissue. A synergic effect of C4 plus benznidazole against epimastigote and trypomastigote forms was observed in vitro, and in the murine model, we observed a substantial reduction in parasitemia levels and lowered mortality rates. These findings encourage supplementary investigations of carboline compounds as potential new Trypanocidal drugs.
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comparative study of the Trypanocidal activity of the methyl 1 nitrophenyl 1 2 3 4 9h tetrahydro β carboline 3 carboxylate derivatives and benznidazole using theoretical calculations and cyclic voltammetry
European Journal of Medicinal Chemistry, 2009Co-Authors: Lilian Tatiani Dusman Tonin, Celso Vataru Nakamura, Valeria Aquilino Barbosa, Cleverson C Bocca, Erika R F Ramos, Willian Ferreira Da Costa, Ernani A Basso, Tânia Ueda Nakamura, Maria Helena SarragiottoAbstract:The cis and trans isomers of methyl 1-(m-nitro)phenyl and 1-(p-nitro)phenyl-1,2,3,4-tetrahydro-9H-beta-carboline-3-carboxylates (compounds 3a,b, 4a and b) were synthesized and evaluated in vitro against epimastigote forms of Trypanosoma cruzi. Among all of the evaluated tetrahydro-beta-carboline derivatives, the compound trans-methyl 1-(m-nitro)phenyl-1,2,3,4-9H-tetrahydro-beta-carboline-3-carboxylate (3b) was found to exhibit significant Trypanocidal activity (IC(50)=22.2 microM). Theoretical studies of molecular conformations and electronic properties for the synthesized compounds and benznidazole, as well as, the cyclic voltammetric (CV) behaviors' determination were performed. A comparative study of the Trypanocidal activity of the nitrophenyl-tetrahydro-beta-carbolines derivatives and benznidazole, using the results of theoretical calculations and of the cyclic voltammetry experiments, is presented.
