Design, Synthesis, and Biological Evaluation of 2-Phenoxyalkylhydrazide Benzoxazole Derivatives as Quorum Sensing Inhibitors with Strong Antibiofilm Effect.

With the increasing problem of bacterial resistance to traditional antibiotics, there is an urgent need for new antibacterial agents with novel mechanisms to treat infections caused by drug-resistant bacteria. In this paper, we designed and synthesized 2-phenoxyalkylhydrazide benzoxazole derivatives and evaluated their quorum sensing inhibition activity. Among them, 26c at a concentration of 102.4 µg/mL not only inhibited the production of pyocyanin and rhamnolipid by 45.6% and 38.3%, respectively, but also suppressed 76.6% of biofilm production at 32 µg/mL. In addition, 26c did not affect bacterial growth, but in a mouse model infected with P. aeruginosa PAO1, it could help ciprofloxacin effectively eliminate the living bacteria. In the targeting experiment, 26c could inhibit the fluorescence intensity of PAO1-lasB-gfp and PAO1-pqsA-gfp in a concentration-dependent manner, indicating that the compound acts on the quorum sensing system. Overall, 26c is worthy of further investigation as a quorum sensing inhibitor with strong antibiofilm effect.

5-Hydroxymethylfurfural induces mice frailty through cell senescence-associated sarcopenia caused by chronic inflammation.

Objective: 5-Hydroxymethylfurfural (5-HMF) is an important component of air pollution, confirmed to be a risk factor for pulmonary inflammation. However, its association with general health is unknown. This article aimed to clarify the effect and mechanism of 5-HMF in the occurrence and aggravation of frailty in mice by investigating whether exposure to 5-HMF was linked to the occurrence and aggravation of mice frailty. Methods: Twelve male C57BL/6 mice (12-month-old, 38 ± 1 g) were randomly divided into the control group and the 5-HMF group. The 5-HMF group was treated with 5-HMF (1 mg/kg/day, respiratory exposure) for 12 months, whereas the control group was treated with equal amounts of sterile water. After the intervention, the ELISA method was used to detect the serum inflammation level of the mice, and the physical performance and frail status were evaluated using a Fried physical phenotype-based assessment tool. The differences in the body compositions were calculated from their MRI images, and the pathological changes in their gastrocnemius muscle were revealed using the H&E staining. Furthermore, the senescence of skeletal muscle cells was evaluated by measuring the expression levels of senescence-related proteins by the western blotting. Results: In the 5-HMF group, serum inflammatory factors IL-6, TNF-α, and CRP levels were significantly raised (p < 0.01). Mice in this group had higher frailty scores and significantly reduced grip strength (p < 0.001), slower weight gains, less WVgastrocnemius muscle masses, and lower sarcopenia indices (SI). In addition, the cross-sectional areas of their skeletal muscles were reduced, and the levels of their cell senescence-related proteins (p53, p21, p16, SOD1, SOD2, SIRT1, SIRT3) were considerably altered (p < 0.01). Conclusion: 5-HMF may induce chronic and systemic inflammation, which in turn accelerates the progression of the frailty of mice through cell senescence.

Discovery of 1,2,3-selenadiazole analogues as antifungal agents using a scaffold hopping approach.

With the increasing incidence of antifungal resistance, new antifungal agents having novel scaffolds hence are in an urgent need to combat infectious diseases caused by multidrug-resistant (MDR) pathogens. In this study, we reported the design, synthesis, and pharmacological evaluation of novel 1,2,3-selenadiazole analogues by scaffold hopping strategy. Preliminary results of antifungal activity demonstrated that the new class of compounds showed broad-spectrum fungistatic and fungicidal activity. Most importantly, these newly synthesized compounds can eliminate these azole-resistant fungi and inhibit the formation of C. albicans biofilm. In particular, compound S07 showed promising antifungal activity against five azole-resistant strains with MIC values ranging from 4 to 32 µg/mL. Then, further target identification and mechanistic studies indicated that representative compound S07 exert its inhibitory activity by inhibiting fungal lanosterol 14α-demethylase enzyme (CYP51). Interestingly, representative compounds showed low cytotoxicity on mammalian cell lines. In addition, the molecular docking studies elucidated the binding modes of these compounds toward CYP51. Altogether, these results suggest that compound S07 with novel skeleton is a promising CYP51 inhibitor for treatment of fungal infections.