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 6o 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 6o 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, 6o elevated mitochondrial nitric oxide (NO) and reactive oxygen species (ROS) levels, exacerbating cellular damage. 6o also displayed low hERG channel toxicity, favorable in vivo safety, and acceptable solubility. In summary, 6o 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.