mannich-bases and Chagas-Disease

The protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, the most important parasitic infection in Latin America. The only treatments currently available are nitro-derivative drugs that are characterised by high toxicity and limited efficacy. Therefore, there is an urgent need for more effective, less toxic therapeutic agents. We have previously identified the potential for Mannich base derivatives as novel inhibitors of this parasite. To further explore this family of compounds, we synthesised a panel of 69 new analogues, based on multi-parametric structure-activity relationships, which allowed optimization of both anti-parasitic activity, physicochemical parameters and ADME properties. Additionally, we optimized our in vitro screening approaches against all three developmental forms of the parasite, allowing us to discard the least effective and trypanostatic derivatives at an early stage. We ultimately identified derivative 3c, which demonstrated excellent trypanocidal properties, and a synergistic mode of action against trypomastigotes in combination with the reference drug benznidazole. Both its druggability and low-cost production make this derivative a promising candidate for the preclinical, in vivo assays of the Chagas disease drug-discovery pipeline.

Topics: Benzimidazoles; Cell Line; Cell Proliferation; Chagas Disease; Drug Design; Humans; Imidazoles; Life Cycle Stages; Mannich Bases; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease is a neglected chronical parasitosis caused by the parasite Trypanosoma cruzi (T. cruzi). Nine ferrocenyl Mannich base derivatives were synthetized and characterized to explore their in vitro activity on three T. cruzi strains of the parasite and their cytotoxicity on Vero cells to calculate the selectivity index (SI). Compound 2, 1-ferrocenyl-3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)propan-1-one, stood out as the most promising derivative showing a half maximal inhibitory concentration (IC

Topics: Animals; Chagas Disease; Chlorocebus aethiops; Glucose Metabolism Disorders; Mannich Bases; Molecular Docking Simulation; Protein Binding; Superoxide Dismutase; Trypanocidal Agents; Trypanosoma cruzi; Vero Cells

The current chemotherapy against Chagas disease is inadequate and insufficient. A series of ten Mannich base-type derivatives have been synthesized to evaluate their in vitro antichagasic activity. After a preliminary screening, compounds 7 and 9 were subjected to in vivo assays in a murine model. Both compounds caused a substantial decrease in parasitemia in the chronic phase, which was an even better result than that of the reference drug benznidazole. In addition, compound 9 also showed better antichagasic activity during the acute phase. Moreover, metabolite excretion, effect on mitochondrial membrane potential and the inhibition of superoxide dismutase (SOD) studies were also performed to identify their possible mechanism of action. Finally, docking studies proposed a binding mode of the Fe-SOD enzyme similar to our previous series, which validated our design strategy. Therefore, the results suggest that these compounds should be considered for further preclinical evaluation as antichagasic agents.

Topics: Animals; Cells, Cultured; Chagas Disease; Chlorocebus aethiops; Cyclophosphamide; Dose-Response Relationship, Drug; Humans; Injections, Intraperitoneal; Mannich Bases; Mice; Mice, Inbred BALB C; Molecular Docking Simulation; Molecular Structure; Parasitic Sensitivity Tests; Structure-Activity Relationship; Superoxide Dismutase; Trypanocidal Agents; Trypanosoma cruzi; Vero Cells

Chagas disease is a neglected tropical disease with 6-7 million people infected worldwide, and there is no effective treatment. Therefore, there is an urgent need to continue researching in order to discover novel therapeutic alternatives. We present a series of arylaminoketone derivatives as means of identifying new drugs to treat Chagas disease in the acute phase with greater activity, less toxicity, and a larger spectrum of action than that corresponding to the reference drug benznidazole. Indexes of high selectivity found in vitro formed the basis for later in vivo assays in BALB/c mice. Murine model results show that compounds 3, 4, 7, and 10 induced a remarkable decrease in parasitemia levels in acute phase and the parasitemia reactivation following immunosuppression, and curative rates were higher than with benznidazole. These high antiparasitic activities encourage us to propose these compounds as promising molecules for developing an easy to synthesize anti-Chagas agent.

Topics: Animals; Cells, Cultured; Chagas Disease; Chlorocebus aethiops; Disease Models, Animal; Dose-Response Relationship, Drug; Mannich Bases; Mice; Mice, Inbred BALB C; Molecular Structure; Parasitic Sensitivity Tests; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma cruzi; Vero Cells