Wenfeng Liu

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. Graphical abstract

Herein, we developed a unified strategy to synthesize three libraries of medicinally attractive cycloheptatriene-fused hetero-bicyclo[3.1.1]heptanes (X-BCHeps) through a Lewis acid-catalyzed higher-order [8+3] cycloaddition of bicyclo[1.1.0]butanes (BCBs) with troponoids including azaheptafulvenes, tropones, and tropothiones. This method features excellent periselectivity, simple operation, mild reaction conditions, and high efficiency. Control experiments and DFT calculatioins suggest that the cycloaddition proceeds via a concerted SN2 nucleophilic addition of troponoids to the Lewis acid-activated BCB species I. Scale-up experiments and synthetic transformations further highlight the synthetic utility. We anticipate that our findings will inspire the scientific community and motivate further exciting advances in BCB chemistry.

Long‐term use of naproxen can lead to serious side effects. Inspired by the biological activity of cinnamic acid, a series of cinnamic acid derivatives containing naproxen were designed and synthesized, and their anti‐inflammatory activities and mechanisms were explored in vitro. Our results indicated that all of naproxen derivatives showed more significant inhibition against lipopolysaccharide (LPS)‐induced nitric oxide (NO) production and had a lower degree of cytotoxicity than that of naproxen. The present studies revealed that compound 23 (IC ₅₀ = 5.66 ± 1.66 µM) markedly inhibited the LPS‐induced NO production and the over‐expression of pro‐inflammatory cytokines, including interleukin (IL)‐1β, inducible NO synthase (iNOS), and cyclooxygenase‐2 (COX‐2). Furthermore, it blocked the activation of NF‐κB signaling pathway and pyrin domain‐containing protein 3 (NLRP‐3) inflammasome in a concentration‐dependent manner. Additionally, docking studies confirmed that compound 23 exhibited a well‐fitting into the NLRP3 active site. Considering these results, compound 23 might be a novel NLRP3 inhibitor to treat inflammatory diseases.

Naproxen, widely used to treat anti-inflammatory diseases, would cause serious of side effects. Based on the biological activities of cinnamic acid, naproxen derivatives containing cinnamic acid were designed, synthesized and used to enhance their anti-inflammatory activities and safeties. The results investigated that thirty novel naproxen derivatives had inhibitory effects on the nitric oxide (NO) release in RAW264.7 macrophage cells. A majority of naproxen derivatives showed the lower degree of cytotoxicity than that of naproxen. In vitro studies revealed that A22 (IC50 = 7.38 ± 1.96 µM) blocked the activation of nuclear transcription factor κB (NF-κB) signaling pathway and pyrin domain containing protein 3 (NLRP-3) inflammasome in a concentration dependent manner, thereby down-regulating the expression of pro-inflammatory cytokines, such as interleukin (IL)-1β, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Docking studies confirmed that A22 exhibited a well-fitting into the NLRP3 active site. Accordingly, A22 might be a novel NLRP3 inhibitor to treat inflammatory diseases.

Essential oils (EOs), derived from medicinal plants, has been reported to possess various bioactivities to treat inflammatory diseases. Therefore, it is urgent to investigate the effect and the mechanism of EOs essential oils as naturally anti-inflammatory agents. The present study indicated thirty-one EOs had different inhibition on lipopolysaccharide (LPS)-induced nitric oxide (NO) production. Moreover, the most potent EOs against NO production in BV2 cells were chuan-xiong, schizonepeta tenuifolia, lemongrass and zedoary turmeric with IC₅₀ values of 12.59, 23.12, 22.76 and 21.88 μg/mL, respectively. The further studies revealed that ligustilide, tributyl citrate and longifolene, the main constituents of chuan-xiong EO, schizonepeta tenuifolia EO and zedoary turmeric EO, were responsible for their activities against NO production with IC₅₀ values of 8.75, 6.05 and 20.32 μg/mL. Above all, theses EOs were confirmed to be promising anti-inflammatory agents.

Antibiotics are currently used for the treatment of Helicobacter pylori (H. pylori), which is confirmed to be the major cause of gastric disorders. However, the long-term consumption of antibiotics has already caused antibiotic resistance and side effects in vivo. Therefore, there is an emerging need for searching for safe and effective anti-H. pylori agents. Inspired by the excellent bioactivities of cinnamic acid, a series of cinnamic acid derivatives (compounds 1–30) were synthesized and determined for H. pylori inhibition. The initial screening revealed that compound 23, a 2,4-dinitro cinnamic acid derivative containing 4-methoxyphenol, showed excellent H. pylori inhibition with an MIC value of 4 μM. Further studies indicated that compound 23 showed anti-bacterial activity and had a bactericidal effect on H. pylori due to the destruction of the bacterial structure. Molecular docking analysis revealed that the 2,4-dinitro groups in cinnamic acid moiety formed hydrogen bonding with amino acid residues in an active pocket of H. pylori protein. Interestingly, the ester moiety fitted into the hydrophobic pocket, attaining additional stability to compound 23. Above all, the present study reveals that compound 23 could be considered a promising anti-H. pylori agent to treat H. pylori causing gastritis.