Synthesis of 1,4‐Naphthoquinone‐Benzenesulfonamide Derivatives with Anti‐ <i>H. Pylori</i> Activity and Studies on their Mechanism of Action

Helicobacter pylori exhibits a relatively high infection rate and marked drug resistance; in severe cases, it can even progress to gastric cancer, posing a substantial threat to human health. To address this pressing issue, the synthesis of a series of 1,4-naphthoquinone-benzenesulfonamide derivatives and investigations into their anti-H. pylori activity is reported.The synthesized compounds are characterized by ¹H/¹³C NMR and HRESIMS. Activity evaluation assays reveal that all synthesized compounds exert notable inhibitory effects against H. pylori, with minimum inhibitory concentrations ranging from 4 to 16 μg mL^-1 (positive control: metronidazole, 4 μg mL^-1). Compound 6i induces excessive reactive oxygen species (ROS) production in H. pylori, impairs mitochondrial structure and function, reduces ATP synthesis, and ultimately leads to bacterial death. The reduction of FADH₂ (a key donor for the electron transport chain), electron leakage, and the decreased NADP⁺/NADPH ratio further indicates that compound 6i can disrupt the intracellular redox balance in bacteria. Additionally, reverse transcription quantitative polymerase chain reaction experiments confirm that compound 6i downregulates the expression levels of ROS- and ATP-related genes. Furthermore, molecular docking and molecular dynamics simulation experiments verify that compound 6i can stably bind to the MdaB gene in H. pylori, thereby exerting a downregulatory effect on MdaB. Therefore, the synthesized compound 6i has been confirmed to be a compound capable of disrupting the redox balance and energy metabolism of H . pylori, and this compound may serve as a lead compound against H . pylori.