Pyridyl-Imidazopyridine Derivatives Displaying Submicromolar Activity Against Trypanosoma cruzi

Chagas disease, caused by the protozoan Trypanosoma cruzi (T. cruzi), remains a major public health challenge due to the limited efficacy and high toxicity of current treatments. In this study, we describe the design and synthesis of 10 imidazo[1,2-a]pyridine derivatives as potential antitrypanosomal agents. All compounds were evaluated in vitro against intracellular forms of T. cruzi, and the most active were further assessed for cytotoxicity and cruzain inhibition. Molecular docking studies were also conducted to investigate their binding modes in the enzyme active site. Some pyridyl-substituted derivatives showed high potency, with submicromolar EC₅₀ values. Among them, compound 5h emerged as the most promising, with an EC₅₀ of 0.16 μM, a selectivity index greater than 1250, and an IC₅₀ of 10.6 μM against cruzain. Docking studies highlighted the importance of Cys25, Leu67, Met68, Ala133, and Glu205 in ligand recognition and suggested that chlorine substitution and pyridyl orientation influence cruzain binding. However, the discrepancy between the high cellular activity and the moderate cruzain inhibition, together with the weak inhibition observed for other active derivatives, suggests a likely multitarget mechanism of action. Overall, these findings highlight pyridyl-imidazopyridines as promising scaffolds for the development of new anti-T. cruzi agents.