Discovery of novel cinnamic acid derivatives with anti-Helicobacter pylori mechanism.

With the efficacy of standard anti-Helicobacter pylori (Hp) regimens declining due to increasing resistance and adverse effects, the development of safer alternatives is imperative. Inspired by the bioactivity of cinnamic acid, a series of cinnamic acid derivatives was designed and screened for their activity against Hp. Among the synthesized derivatives, compound 23, bearing a dinitro group, exhibited potent anti-Hp activity with a minimum inhibitory concentration (MIC) of 4 µM, demonstrating a two-fold greater potency than metronidazole. Meanwhile, the quinoline-containing derivative (compound 25) showed activity comparable to that of metronidazole. Compound 23 was highly specific for Hp, showing no efficacy against other gastrointestinal pathogens (MIC > 128 µM). The mechanistic studies indicated that compound 23 could cause severe cellular damage (vesicle formation, swelling, and plasmolysis), disrupt biofilms, and inhibit urease, thereby blocking ammonia cloud formation. Furthermore, it effectively suppressed the production and the overexpression of inflammatory mediators in RAW264.7 cells. Therefore, these results suggested that compound 23 was a viable lead candidate for the treatment of Hp infection.