Mechanistic Exploration of N,N′-Disubstituted Diamines as Promising Chagas Disease Treatments

TL;DR

Researchers explored diamines as potential treatments for Chagas disease, finding some compounds effective against the parasite but needing further refinement.

Contribution

The study introduces a new class of diamines with potential antiparasitic activity and investigates their mechanisms of action.

Findings

Five diamines showed potent activity against T. cruzi amastigotes with short aliphatic linkers.

Compound 3c inhibited polyamine transport in T. cruzi, suggesting a key mechanism.

Fluorescent analogs confirmed intracellular uptake but lacked antiparasitic activity.

Abstract

Introduction: Chagas disease, caused by the protozoan Trypanosoma cruzi, remains a major public health concern due to the limited effectiveness of current treatments, especially in the chronic stage. Objective: Here, we wanted to advance a library of 30 N,N′-disubstituted diamines as promising antichagasic agents and gain insight into the mechanism of action. Methods: The library was evaluated for activity against the T. cruzi amastigote stage and trypanocidal efficacy. In addition, selected compounds were tested as potential polyamine transport inhibitors, and a fluorescent analog was employed to investigate compound internalization. Results: Five compounds exhibited potent activity (pIC50 > 6.0), particularly those with short aliphatic linkers (3–6 carbon atoms), suggesting a structure–activity relationship favouring shorter chains. Mechanistic studies showed that compound 3c strongly inhibited polyamine transport, a vital pathway in T. cruzi, though this was not a universal mechanism among active hits, indicating the potential for multiple targets. A fluorescent analog confirmed intracellular uptake in amastigotes but lacked antiparasitic activity, likely due to disrupted pharmacophoric features. Importantly, none of the compounds demonstrated trypanocidal activity in long-term assays, and some showed cytotoxicity, particularly in the benzyloxy-substituted series. Conclusions: These findings position N,N′-disubstituted diamines as a viable scaffold for Chagas disease drug discovery. However, further optimization is required to enhance selectivity, achieve trypanocidal effects, and better understand the underlying mechanisms of action.

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