Due to the prolonged misuse of antimicrobial agents and the development of various resistance mechanisms, Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a leading threat to the public health. The production of a penicillin binding protein 2a (PBP2a) plays a crucial role in cell wall synthesis of MRSA, and conformational alterations in PBP2a impede the effective binding of β-lactam antibiotics, the most effective class of antibiotic, to the active site. The PBP2a allosteric site located 60 Å from the active site, and binding of allosteric site significantly influences the conformational dynamics of the active site. Based on the effect of nucleoside which re-sensitizes MRSA to β-lactam antibiotics, we conducted extensive virtual screening to design and synthesize a series of novel nucleoside inhibitors targeting the allosteric site of MRSA PBP2a. These inhibitors exhibit a distinct chemical structure compared to existing clinical antibiotics. Notably, compound 13e demonstrated a minimum inhibitory concentration (MIC) of 16 µg/mL against MRSA strain, showcasing superior antibacterial activity relative to the reference antibiotic. Time-kill curve indicated that compound 13e effectively inhibit bacterial growth. Interestingly, a synergistic effect was observed at low concentrations of compound 13e in combination treatment with Oxacillin, whereas antagonism occurred at higher concentrations of compound 13e. The morphological observation showed the integrity of the bacterial cell wall was disrupted after compound 13e treatment, and it exhibited a lower propensity for developing resistance compared to cephalosporin. Additionally, this compound did not affect the viability of normal human intestinal epithelial cells (HIEC) and brain microvascular endothelial cells at concentration much higher than MIC. Over all, this unique antibacterial mechanism underscores the optimization potential of these nucleoside compounds, providing new perspectives and methodologies for the development of novel antimicrobial agents.

2024-09-01·Acta Pharmacologica Sinica

Discovery and pharmacological characterization of 1,2,3,4-tetrahydroquinoline derivatives as RORγ inverse agonists against prostate cancer

Article

作者: Chen, Xiao-Shan ; Wu, Tong ; Hu, Qing-Qing ; Shen, Hui ; Luo, Xiao-Yu ; Lu, Zhi-Fang ; Li, Cheng-Chang ; Zhang, Yan ; Zhang, Cheng ; Wu, Xi-Shan ; Xu, Yong ; Peng, Chao ; Zhao, Xiao-Fan ; Yu, Hao-Nan

The retinoic acid receptor-related orphan receptor γ (RORγ) is regarded as an attractive therapeutic target for the treatment of prostate cancer. Herein, we report the identification, optimization, and evaluation of 1,2,3,4-tetrahydroquinoline derivatives as novel RORγ inverse agonists, starting from high throughput screening using a thermal stability shift assay (TSA). The representative compounds 13e (designated as XY039) and 14a (designated as XY077) effectively inhibited the RORγ transcriptional activity and exhibited excellent selectivity against other nuclear receptor subtypes. The structural basis for their inhibitory potency was elucidated through the crystallographic study of RORγ LBD complex with 13e. Both 13e and 14a demonstrated reasonable antiproliferative activity, potently inhibited colony formation and the expression of AR, AR regulated genes, and other oncogene in AR positive prostate cancer cell lines. Moreover, 13e and 14a effectively suppressed tumor growth in a 22Rv1 xenograft tumor model in mice. This work provides new and valuable lead compounds for further development of drugs against prostate cancer.

2024-01-25·Journal of Medicinal Chemistry1区 · 医学

Discovery of Natural Ah Receptor Antagonists from Salvia miltiorrhiza Bunge and Synthesis of Analogs for Tumor Immunotherapy

1区 · 医学

Article

作者: Jiang, Jianshuang ; Yang, Yanan ; Li, Zhenyuan ; Yuan, Xiang ; Zhang, Xu ; Jin, Jing ; Li, Shuying ; Du, Rongrong ; Chen, Xiaoguang ; Xue, Nina ; Zhang, Peicheng ; Gu, Quanchang ; Xing, Zeyu

IDO/TDO/Kyn/AhR signaling plays a crucial role in regulating innate and adaptive immunity, and targeting Ah receptor (AhR) inhibition can potentially redirect immune cells toward an antitumoral phenotype. Therefore, AhR is an attractive drug target for novel small molecule cancer immunotherapies. In this study, natural products tanshinolic A-D (1-4), the first adducts composed of ortho-naphthoquinone-type tanshinone and phenolic acid featuring a unique 1,4-benzodioxan hemiacetal structure, were isolated and characterized from the roots of Salvia miltiorrhiza Bunge. Luciferase reporter gene assay revealed that these adducts exhibited significant AhR inhibitory activity. A linear strategy was developed to construct a cis-3,4-disubstituted 1,4-benzodioxan hemiacetal structure. Encouragingly, in both in vitro and in vivo experiments, (±)-13e demonstrated the ability to inhibit tumor cell proliferation, promote INF-γ secretion in CD8⁺ T cells, and inhibit PD-1/PD-L1 signal transduction, which could exert tumor inhibition properties by inhibiting AhR activity, positioning it as a promising candidate for tumor immunotherapy.

100 项与 (±)-13e(北京协和医院) 相关的药物交易

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