# Discovery of Niclosamide Analogs with Potent Mitochondrial Uncoupling Activity and Reduced Mitochondrial Inhibition–Associated Toxicity

## TL;DR

Researchers improved niclosamide, a drug that disrupts mitochondria, to make it more effective and less toxic for cancer treatment.

## Contribution

The study introduces niclosamide analogs with broader therapeutic windows and reduced toxicity through structural optimization.

## Key findings

- Several niclosamide analogs sustained mitochondrial uncoupling at higher concentrations without respiratory inhibition.
- QSAR analysis linked electronic and hydrophobic properties of analogs to improved therapeutic index.
- Niclosamide analogs like Nic-2 and Nic-8 showed prolonged uncoupling and reduced cytotoxicity.

## Abstract

Niclosamide, an FDA-approved anthelmintic, functions
as a mitochondrial
uncoupler with promising anticancer potential, yet its efficacy remains
limited, often ascribed to poor bioavailability. We identify a more
fundamental constraintits narrow therapeutic window arising
from a biphasic mechanism that promotes uncoupling at low doses but
inhibits respiration at higher doses. To overcome this limitation,
we synthesized 30 niclosamide analogs, systematically profiled their
mitochondrial responses using Seahorse MitoTox assay, and developed
QSAR models to uncover structural determinants of efficacy and toxicity.
Niclosamide exhibited a narrow uncoupling range (0.5–1 μM)
beyond which respiration was suppressed. Several analogs, including
Nic-2, Nic-8, Nic-40, and Nic-43, sustained uncoupling for up to 9
h at concentrations up to 10 μM, with some showing improved
signal modulation and reduced cytotoxicity. QSAR analysis revealed
that substitution electronic properties and ring-specific hydrophobicity
are related to the therapeutic index. These findings expand niclosamide’s
therapeutic window through rational scaffold tuning, enabling safer
mitochondrial reprogramming strategies for cancer therapy.