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

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.