Wang Yang, Qian Shihu, Zhao Fang, Wang Yujie, Li Jiaming
College of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.
Institute of Medicinal Chemistry, Anhui Academy of Chinese Medicine, Hefei, China.
Front Chem. 2022 Jul 26;10:906974. doi: 10.3389/fchem.2022.906974. eCollection 2022.
Nitrogen-containing heterocyclic compounds have shown promising therapeutic effects in a variety of inflammatory and neurodegenerative diseases. Recently, terazosin (TZ), a heterocyclic compound with a quinazoline core, was found to combine with phosphoglycerol kinase 1 (Pgk1) and protect neurons by enhancing Pgk1 activity and promoting glycolysis, thereby slowing, or preventing the neurodegeneration of PD. These findings indicated that terazosin analogs have bright prospects for the development of PD therapeutics. In this study, a series of terazosin analogs were designed and synthesized for neuroprotective effects by targeting Pgk1. Among them, compound was obtained with the best Pgk1 agonistic activity and neuroprotective activity. Further study indicates that it can increase intracellular ATP content and reduce ROS levels by stimulating the activity of Pgk1, thereby playing a role in protecting nerve cells. In conclusion, this study provides a new strategy and reference for the development of neuroprotective drugs.
含氮杂环化合物在多种炎症和神经退行性疾病中显示出有前景的治疗效果。最近，发现具有喹唑啉核心的杂环化合物特拉唑嗪（TZ）与磷酸甘油激酶1（Pgk1）结合，并通过增强Pgk1活性和促进糖酵解来保护神经元，从而减缓或预防帕金森病（PD）的神经退行性变。这些发现表明特拉唑嗪类似物在PD治疗药物开发方面具有光明前景。在本研究中，设计并合成了一系列以Pgk1为靶点的具有神经保护作用的特拉唑嗪类似物。其中，化合物 具有最佳的Pgk1激动活性和神经保护活性。进一步研究表明，它可通过刺激Pgk1的活性来增加细胞内ATP含量并降低ROS水平，从而在保护神经细胞中发挥作用。总之，本研究为神经保护药物的开发提供了新策略和参考。
