Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea; Division of Bio-Medical Science & Technology, University of Science and Technology, Daejeon, 34113, Republic of Korea.
Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea.
Eur J Med Chem. 2023 Aug 5;256:115433. doi: 10.1016/j.ejmech.2023.115433. Epub 2023 May 5.
Many studies have reported that chalcone-based compounds exhibit biological activities such as anticancer, antioxidant, anti-inflammatory and neuroprotective effects. Among the published chalcone derivatives, (E)-1-(3-methoxypyridin-2-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one (VEDA-1209), which is currently undergoing preclinical study, was selected as a starting compound for the development of new nuclear factor erythroid 2-related factor 2 (Nrf2) activators. Based on our previous knowledge, we attempted to redesign and synthesize VEDA-1209 derivatives by introducing the pyridine ring and sulfone moiety to ameliorate its Nrf2 efficacy and drug-like properties. Among the synthesized compounds, (E)-3-chloro-2-(2-((3-methoxypyridin-2-yl)sulfonyl)vinyl) pyridine (10e) was found to have approximately 16-folds higher Nrf2 activating effects than VEDA-1209 (10e: EC = 37.9 nM vs VEDA-1209: EC = 625 nM) in functional cell-based assay. In addition, 10e effectively improved drug-like properties such as CYP inhibition probability and metabolic stability. Finally, 10e demonstrated excellent antioxidant and anti-inflammatory effects in BV-2 microglial cells and significantly restored spatial memory deficits in lipopolysaccharide (LPS)-induced neuroinflammatory mouse models.
许多研究报告表明，查耳酮类化合物具有生物活性，如抗癌、抗氧化、抗炎和神经保护作用。在已发表的查耳酮衍生物中，（E）-1-（3-甲氧基吡啶-2-基）-3-（2-（三氟甲基）苯基）-2-烯-1-酮（VEDA-1209）目前正在进行临床前研究，被选为开发新核因子红细胞 2 相关因子 2（Nrf2）激活剂的起始化合物。基于我们之前的知识，我们试图通过引入吡啶环和砜基来重新设计和合成 VEDA-1209 衍生物，以改善其 Nrf2 功效和类药性。在所合成的化合物中，（E）-3-氯-2-（2-（（3-甲氧基吡啶-2-基）砜基）乙烯基）吡啶（10e）在功能性基于细胞的测定中被发现比 VEDA-1209（10e：EC=37.9 nM 对 VEDA-1209：EC=625 nM）具有约 16 倍更高的 Nrf2 激活作用。此外，10e 有效改善了类药性，如 CYP 抑制概率和代谢稳定性。最后，10e 在 BV-2 小胶质细胞中表现出优异的抗氧化和抗炎作用，并显著恢复脂多糖（LPS）诱导的神经炎症小鼠模型中的空间记忆缺陷。
