Discovery of Niclosamide Analogs with Potent Mitochondrial Uncoupling Activity with reduced toxicity

Mitochondrial uncouplers have shown clinical potential across various diseases, including cancer. Niclosamide, an FDA-approved anthelmintic drug, acts as a mild mitochondrial uncoupler and has demonstrated anticancer activity in multiple preclinical cancer models. However, its clinical application remains limited, with some attributing this to poor bioavailability, while the underlying mechanisms are still unclear. Here, we demonstrate that niclosamide exhibits a dose-dependent biphasic effect, promoting uncoupling at low concentration while acting as a mitochondrial inhibitor at high concentration, which could restrict its therapeutic window and limit efficacy. To overcome this challenge, we aimed to develop next-generation mitochondrial uncouplers (MUs) by synthesizing and evaluating novel Niclosamide derivatives with enhanced therapeutic potential. Through structural modifications, we optimized uncoupling activity while reducing inhibitory toxicity, thereby expanding the pharmacological window. Our findings suggest that fine-tuning the molecular structure of mitochondrial uncouplers could provide a safer and more effective metabolic reprogramming strategy for cancer treatment.