# Contribution to the Chemotherapy of Human Trypanosomiasis: Design, Synthesis, and Biological Evaluation of Dimeric 2‑Nitroimidazoles against Trypanosoma cruzi Amastigotes and Bloodstream Trypanosoma brucei

## TL;DR

Scientists designed new dimeric compounds that effectively target parasites causing Chagas disease and sleeping sickness with low toxicity.

## Contribution

The study introduces dimeric 2-nitroimidazoles with longer linkers that show enhanced potency and selectivity against trypanosomes.

## Key findings

- Longer-chain dimeric compounds showed remarkable potency against Trypanosoma cruzi amastigotes with IC50 < 1.0 μM.
- The compounds demonstrated significant activity against T. b. brucei and low cytotoxicity in mammalian cells.
- The design strategy improved interaction with TcNTR, enhancing bioactivation of the compounds.

## Abstract

Effective and safe
treatments for neglected tropical
diseases caused
by parasites, such as Chagas disease and sleeping sickness, remain
lacking, posing a significant challenge for researchers worldwide.
The rational design of dimeric compounds inspired solely by the pharmacophoric
core of benznidazole (2-nitroimidazole) has proven to be a promising
strategy for antiparasitic development. Thus, in the present work,
it was increased the linker between the active units (2-nitroimidazole)
to improve the interaction with TcNTR, facilitating the bioactivation
of the longest dimers. Biological assays confirmed this, demonstrating
that all compounds were active against replicative intracellular amastigotes
of Trypanosoma cruzi (Tulahuen C2C4-LacZ). Notably, longer-chain dimers exhibited remarkable
potency (IC50 < 1.0 μM). These compounds also
showed significant activity against T. b. brucei and demonstrated very low cytotoxicity in mammalian cells, highlighting
their selectivity, especially among the longer-chain dimers. These
findings support the development of dimeric 2-nitroimidazole derivatives
as selective agents against trypanosomes.