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

Abstract

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-␤-carboline compound N-butyl-1-(4-dimethylamino)phenyl-1,2,3,4-tetrahydro-␤-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. C hagas' disease is an illness that affects around 15 million people on the American continent, and in Brazil, there are an estimated 3 million people infected with Trypanosoma cruzi, the causative agent of this disease (31).The currently available treatment is by two nitroheterocyclic drugs, nifurtimox and benznidazole (BZ), but both are unsatisfactory. Moreover, in Brazil, only BZ is available (19). In this context, new drugs or new therapeutic approaches must be developed. We recently reported that the tetrahydro-␤-carboline compound N-butyl-1-(4-dimethylamino)phenyl-1,2,3,4-tetrahydro-␤-carboline-3-carboxamide, named C4 (see Fig. 3), showed a strong in vitro trypanocidal effect (29).For the treatment of many infectious diseases, therapeutic associations are adopted, with very successful results. Previous works have shown the importance of combination therapy against several microorganisms such as bacteria (17,22,25), fungi (7,13,14), and protozoa such as Plasmodium (9, 21, 30), Leishmania (6, 16), and T. cruzi (3,20). In one of the few previous studies that reported synergistic activities of drugs for T. cruzi treatment, good synergistic activity between parthenolide and BZ was demonstrated (20).Therefore, based on the successful results of known therapeutic associations, the goal of this study was to evaluate the in vitro and in vivo trypanocidal activities of C4 associated with different reference drugs (BZ, ketoconazole, and amphotericin B). (ii) Checkerboard assay of effect of C4 on epimastigote and trypomastigote forms of Trypanosoma cruzi. For the checkerboard assay, we evaluated the trypanocidal effect of the compound C4 associated with other drugs (BZ, ketoconazole, and amphotericin B) on ep...

Evaluation of benznidazole treatment combined with nifurtimox, posaconazole or AmBisome® in mice infected with Trypanosoma cruzi strains

“…This approach might improve the efficacy of treatment (by generating additive or synergistic effects on different pharmacological targets) and decrease the likelihood of drug resistance and toxic effects (by reducing the drug dosages or treatment durations used). Several associations of two drugs inducing limited improvements in mice [15][16][17][18][19][20] or in patients [21] have been tested. However, as far as we know, no experimental studies or clinical trials combining the already patented drugs available on the market (BZL, NFX, POS and AMB) have been reported.…”

Quantitative Laser Biospeckle Method for the Evaluation of the Activity of Trypanosoma cruzi Using VDRL Plates and Digital Analysis

“…The assays that are based on viability require a low dose of the test drug and several hours and even days to develop [4]. Therefore, the use of methods that require a short time are useful in avoiding undesired factors such as degradation, biotransformation and other effects on the test drug.…”

N -Butyl-[1-(4-Methoxy)Phenyl-9 H -β-Carboline]-3-Carboxamide Prevents Cytokinesis in Leishmania amazonensis

“…␤-Carboline alkaloids have drawn attention because of their biological activities against parasites of the Trypanosomatidae family, including antitrypanosomal activity (6)(7)(8)(9)(10) and antileishmanial activity (8,(11)(12)(13). A recent study demonstrated the antileishmanial and antitrypanosomal activity of a series of N-alkyl-(1-phenyl-substituted-tetrahydro-␤-carboline)-3-carboxamides, showing that compounds containing Nbutylcarboxamide groups were the most active, suggesting that these groups may improve the biological activity of these compounds (8).…”