# Cytotoxicity and Antimicrobial Activity of GaMF1 Analogs

## TL;DR

Scientists modified a compound originally targeting tuberculosis to reduce its toxicity and found it also works well against certain parasites and cancer cells.

## Contribution

Structural modifications of GaMF1 reduced cytotoxicity and revealed new antiparasitic and antiproliferative properties.

## Key findings

- Structural modifications of GaMF1 reduced its cytotoxicity against human cells.
- Some GaMF1 analogs showed strong antiparasitic activity against Trypanosoma species.
- Selected derivatives exhibited antiproliferative effects against tumor cell lines.

## Abstract

Recent studies have identified the mycobacterial adenosine triphosphate synthase inhibitor GaMF1 and its structural analogs as compounds with noteworthy antituberculosis activity. Despite these promising results, a significant limitation remains their cytotoxicity against human cells, which, in its current state, overshadows the therapeutic potential. Therefore, addressing this off‐target toxicity is essential for the further development of these compounds as viable drug candidates. In this study, we systematically explored structural modifications of the original GaMF1 scaffold with the primary aim of reducing its inherent cytotoxicity. Individual regions of the parent structure were progressively replaced, enabling the identification of substituents that effectively attenuate cytotoxic effects. Importantly, these structural refinements also led to the emergence of pronounced antiparasitic activity, particularly against trypanosomal species such as Trypanosoma cruzi, Trypanosoma brucei brucei, and Trypanosoma brucei rhodesiense. These findings suggest that the biological potential of this compound class extends beyond what has previously been described. Furthermore, we evaluated the cytotoxicity of selected derivatives against a panel of tumor cell lines, where some compounds showed encouraging antiproliferative effects.

GaMF1 is a reported, highly potent inhibitor of mycobacterial ATP synthase. Structural modification of this scaffold significantly changes biological activity. We present GaMF1 analogues with strong antiparasitic effects, potential antiproliferative properties, and discuss the selectivity limitations of the parent compound and its analogues. Notably, our most active compounds demonstrate higher activity against Trypanosoma cruzi than drugs used to treat Chagas disease.© 2026 WILEY‐VCH GmbH