# Chalcogen Derivatives for the Treatment of African Trypanosomiasis: Biological Evaluation of Thio- and Seleno-Semicarbazones and Their Azole Derivatives

## TL;DR

Researchers designed new compounds to treat African trypanosomiasis by replacing sulfur with selenium, finding some are more effective and less toxic.

## Contribution

The study introduces selenosemicarbazone derivatives as more effective and less toxic alternatives to traditional thiosemicarbazones against T. brucei.

## Key findings

- Selenium-based compounds showed better activity against T. brucei than sulfur-based ones.
- Selenazole ring structures reduced selenium-related toxicity.
- Combining TbrCATL inhibition with antioxidant activity is key for effective treatment.

## Abstract

Human African trypanosomiasis
(HAT) is caused by Trypanosoma brucei. Drug therapy remains challenging
due to drug resistance and/or toxicity. New drugs are needed. Using
thiosemicarbazones as a starting point, we employed a S to Se isosteric replacement strategy to design
44 analogs which were evaluated against T. brucei
in vitro. Compounds were divided into 11 groups
of four derivatives corresponding to thio-, selenosemicarbazones,
and their cyclic counterparts, thio- and selenazoles. We selected
three groups which contained a total of six derivatives that inhibited
parasite growth by >70%. Then, we investigated the mechanism of
action
of these compounds, performing quantitative assays to measure their
inhibition of the T. brucei cathepsin
L-like protease (TbrCATL) and DPPH antioxidant activities.
The lead compound (SeO3) showed antioxidant capacity
and the best activity against T. brucei (EC50 = 0.47 μM). Nevertheless, its toxicity should
be improved. We also predicted the interactions of these compounds
with TbrCATL utilizing molecular dynamics. We demonstrate
that the Se derivatives are more active than their S analogues, and that the selenazole ring decreases Se-associated toxicity. Also, thio- and selenosemicarbazones
are more potent against TbrCATL than the cyclic derivatives.
We conclude that TbrCATL inhibition should be combined
with antioxidant activity to obtain active compounds against T. brucei.