2. Academic Validation
  3. Optimization and evaluation of pyridinyl vinyl sulfones as Nrf2 activator for the antioxidant and anti-inflammatory effects

Optimization and evaluation of pyridinyl vinyl sulfones as Nrf2 activator for the antioxidant and anti-inflammatory effects

  • Eur J Med Chem. 2023 Aug 5;256:115433. doi: 10.1016/j.ejmech.2023.115433.
Byungeun Kim 1,  Rium Kim 1,  Hyeon Jeong Kim 2,  Yoowon Kim 3,  Sun Jun Park 4,  Elijah Hwejin Lee 1,  Jushin Kim 3,  Jaehwan Kim 1,  Ji Won Choi 5,  Jong-Hyun Park 6,  Ki Duk Park 7
Affiliations

Affiliations

  • 1 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.
  • 2 Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea.
  • 3 Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea; Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea.
  • 4 Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea; Cureverse Co., Ltd., KIST, 1st Floor, H2 Building, Seoul, 02792, Republic of Korea.
  • 5 Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea; Cureverse Co., Ltd., KIST, 1st Floor, H2 Building, Seoul, 02792, Republic of Korea. Electronic address: jiwon0602@kist.re.kr.
  • 6 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. Electronic address: jhyunprk@kist.re.kr.
  • 7 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. Electronic address: kdpark@kist.re.kr.
PMID: 37187090 DOI: 10.1016/j.ejmech.2023.115433
Abstract

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: EC50 = 37.9 nM vs VEDA-1209: EC50 = 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.

Keywords

Anti-inflammation; Antioxidation; Neuroprotection; Nrf2 activator; Vinyl sulfone.

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