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

• Published in: European journal of medicinal chemistry Vol. 223; p. 113646
• Main Authors: Beltran-Hortelano, Iván, Atherton, Richard L., Rubio-Hernández, Mercedes, Sanz-Serrano, Julen, Alcolea, Verónica, Kelly, John M., Pérez-Silanes, Silvia, Olmo, Francisco
• Format: Journal Article
• Language: English
• Published: Elsevier Masson SAS 05-11-2021
• Subjects: Benzimidazole; Chagas disease; Imidazole; Mannich bases; Neglected tropical diseases; Trypanosoma cruzi; Neglected tropical diseases; Chagas disease; Mannich bases; Imidazole; Benzimidazole; Trypanosoma cruzi
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.113646

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.
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•Imidazole and benzimidazole Mannich bases as new candidates against Chagas disease.•Efficient screening strategy for the evaluation of new 69 Mannich bases against T. cruzi.•A 2′-nitroimidazole derivative identified as candidate to block the infection in vitro.•The 2′-nitroimidazole 3c synergizes with benznidazole in combinatory therapy in vitro.