Novel Hybrids of 3-Substituted Coumarin and Phenylsulfonylfuroxan as Potent Antitumor Agents against Wild-Type and Drug-Resistant Nonsmall Cell Lung Cancer Cell Lines

Lung cancer represents a major global health challenge, and the development of new therapeutic agents remains a serious task. This study designed and synthesized 27 novel coumarin-furoxan hybrids. Among them, compound <b>6o</b> exhibited potent nanomolar-level antiproliferative activity against six nonsmall cell lung cancer (NSCLC) cell lines, including both wild-type and drug-resistant models. Mechanistic investigations revealed that <b>6o</b> downregulates the expression of ferroptosis-related factors SLC7A11 and GPX4, thereby disrupting redox homeostasis, depleting glutathione, and accumulating lipid peroxides, which collectively trigger ferroptosis. Furthermore, <b>6o</b> elevated mitochondrial nitric oxide (NO) and reactive oxygen species (ROS) levels, exacerbating cellular damage. <b>6o</b> also displayed low hERG channel toxicity, favorable in vivo safety, and acceptable solubility. In summary, <b>6o</b> demonstrates high efficacy against both wild-type and drug-resistant NSCLC cells via a ferroptosis-mediated mechanism, along with a promising safety profile, supporting its potential as a candidate for further development.