Structure–activity relationships study of <i>N</i> -ethylene glycol-comprising alkyl heterocyclic carboxamides against A549 lung cancer cells

<b>Aim:</b> Certain cancer cells depend on oxidative phosphorylation for survival; thus, inhibiting this process may be a promising treatment strategy. This study explored the structure-activity relationships of the mitochondrial inhibitor <i>N</i>-ethylene glycol-comprising alkyl thiophene-3-carboxamide <b>3</b>.<b>Methods & results:</b> We synthesized and evaluated 13 analogs (<b>5a</b>-<b>m</b>) with different ethylene glycol units, heterocycles and connecting groups for their growth-inhibitory effects on A549 non-small cell lung cancer cells. We found that increasing the number of ethylene glycol units significantly enhanced inhibitory activity. Some analogs activated adenosine monophosphate-activated protein kinase, similar to <b>3</b>. Notably, analog <b>5e</b>, which contains tetraethylene glycol units, significantly inhibited tumor growth <i>in vivo</i>.<b>Conclusion:</b> Analog <b>5</b> may be a potential therapeutic agent for non-small cell lung cancer treatment.