Design and synthesis of Mannich base-type derivatives containing imidazole and benzimidazole as lead compounds for drug discovery in Chagas Disease

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