Synthesis of Marine-Inspired Multifaceted DNA Damaging Spirooxindoles Combating NSCLC and Associated Bacterial Infection

Targeted therapeutics have gained prominence in combating non-small cell lung carcinoma (NSCLC) and opportunistic bacterial infections like <i>Staphylococcus aureus</i> (<i>S. aureus</i>). This study explores dual-acting marine-inspired spirooxindoles to limit NSCLC and opportunistic bacteria. Pharmacophoric motifs from antitumor and antibacterial marine products were merged into a new series of pyrazole-clubbed spirooxindoles via a stereoselective [3 + 2] cycloaddition reaction. MTT screening identified <b>4e</b>, <b>4i</b>, and <b>4p</b>-<b>4s</b> as potent cytotoxic agents, with <b>4p</b> showing exceptional activity (IC₅₀ = 0.042 μM) and tumor selectivity (SI = 58.28). <b>4p</b> exhibited antibacterial efficacy against <i>S. aureus</i> (MIC = 25 μg/mL). DNA damage studies using a terbium(III) chloride biosensor revealed <b>4p</b>'s ability to damage both calf thymus and <i>S. aureus</i> DNA at low concentrations. Docking simulations presumed that <b>4p</b> binds between DNA strands, while apoptosis studies indicated it induced G1/S phase cell cycle arrest and increased A549 apoptosis by 33.65%. These findings highlight <b>4p</b> as a promising lead for further studies.