Design, Synthesis, and Biological Evaluation of Acid-Responsive Bifunctional Molecules with Dual Anti-Helicobacter...

The increasing antibiotic resistance of Helicobacter pylori necessitates novel therapeutics. Although rifabutin demonstrates potent anti-H. pylori activity and low resistance rates, its clinical use is limited by myelosuppressive risk. Clinical evidence indicates that vonoprazan acts synergistically with rifabutin, allowing a reduced dosage and duration while maintaining efficacy. We developed acid-responsive bifunctional molecules conjugating both drugs for coordinated gastric release and enhanced local synergy, enabling reduced-dose or shorter-duration therapy with minimal adverse effects. Compound 10, incorporating acid-labile silyl ether and self-immolative linkers, demonstrated potent anti-H. pylori activity (MIC ≤ 0.125 μg/mL) and strong acid suppression (>85% inhibition at 2 mg/kg). In murine models, compound 10 exhibited antiulcer efficacy comparable to vonoprazan at half the dose, with pharmacokinetic analysis revealing minimal systemic exposure to rifabutin, thereby substantially reducing the risk of myelosuppression. This strategy provides a promising approach for effective and safe H. pylori therapy.