2. Academic Validation
  3. Synthesis of dolutegravir derivatives modified by 1,2,3-triazole structure and their anti-inflammatory activity in LPS-induced BV2 cells

Synthesis of dolutegravir derivatives modified by 1,2,3-triazole structure and their anti-inflammatory activity in LPS-induced BV2 cells

  • Bioorg Med Chem Lett. 2025 Mar 1:117:130076. doi: 10.1016/j.bmcl.2024.130076.
Xixi Hou 1,  Longfei Mao 2,  Xuanwei Zhang 3,  Xi Wang 4,  Lan Wang 3,  Jianji Wang 5
Affiliations

Affiliations

  • 1 Key Laboratory of Green Chemical Media and Reactions (Ministry of Education), Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, PR China; Department of Pharmacy, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan 471003, PR China.
  • 2 College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, Henan 471000, PR China. Electronic address: longfeimao2022@163.com.
  • 3 College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, Henan 471000, PR China.
  • 4 Key Laboratory of Green Chemical Media and Reactions (Ministry of Education), Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, PR China.
  • 5 Key Laboratory of Green Chemical Media and Reactions (Ministry of Education), Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, PR China. Electronic address: jwang@htu.edu.cn.
PMID: 39694340 DOI: 10.1016/j.bmcl.2024.130076
Abstract

Given the promising anti-inflammatory activity of the HIV Integrase Inhibitor dolutegravir and the widespread use of the 1,2,3-triazole structure in anti-inflammatory drug development, this study aimed to enhance dolutegravir's efficacy by introducing a 1,2,3-triazole group. As a result, four series of dolutegravir derivatives were synthesized. Screening these derivatives for anti-inflammatory activity in microglial cells revealed that compound 6k demonstrated the most potent anti-inflammatory effect without significant cytotoxicity. Specifically, 6k significantly reduced the transcription levels of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α in lipopolysaccharide (LPS)-induced BV-2 microglial cells. Additionally, 6k decreased the LPS-induced overproduction of inflammatory mediators such as nitric oxide (NO), IL-6, and TNF-α. Further investigation into the upstream inflammatory Enzymes iNOS and COX-2 showed that 6k markedly reduced their transcription and protein levels. To elucidate the mechanism underlying the anti-inflammatory effects of dolutegravir derivatives, it was found that compound 6k modulates microglial inflammation by inhibiting the phosphorylation and nuclear translocation of signal transducer and activator of transcription 1/3 (STAT1/3). Moreover, acute toxicity testing in mice indicated that compound 6k exhibited low toxicity, suggesting its potential as a lead compound for the treatment of neuroinflammation.

Keywords

1,2,3-Triazoles; Anti-inflammatory; Dolutegravir; LPS-induced; STAT1/3.

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