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<p>URAT1 represents a critical therapeutic target for the treatment of hyperuricemia. However, current URAT1 inhibitors are limited by high toxicity and adverse effects, underscoring the urgent need to develop safe and effective therapeutic agents. In this study, nine novel nuciferine derivatives were synthesized by modifying the N7-position substituent to enhance URAT1 inhibitory activity. CCK-8 assays revealed that most compounds exhibited no significant cytotoxicity in HK-2 cells at concentrations up to 60 μM, supporting their suitability for further investigation. Western blot analysis demonstrated that the majority of derivatives downregulated URAT1 protein expression in HK-2 cells, with compound 3-4 exhibiting the most potent inhibition, approaching the efficacy of benzbromarone. Structure-activity relationship (SAR) studies indicated that sulfonyl substituents improved URAT1 inhibition, while aromatic amides reduced activity. Molecular docking showed that 3-4 formed stronger interactions with URAT1 and had higher binding affinity (-6.794 kcal/mol). Molecular dynamics simulations showed that 3-4 formed a stable complex with URAT1. ADME analysis confirmed 3-4 complied with Lipinski’s Rule of Five, featuring balanced lipophilicity and favorable pharmacokinetic properties. These results underscore the N7-position as a key modifiable site for developing nuciferine-based anti-hyperuricemic agents with improved efficacy.</p><p></p>

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Discovery of novel nuciferine-based URAT1 inhibitors for hyperuricemia: synthesis, biological evaluation, and computational insights

  • 期刊论文

  • 发表日期：

    2025年12月1日

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  • Yan-fei Liu,
  • Ze-sheng Hao,
  • Xu Guo,
  • Shu-tao Sun,
  • Mu-xuan Wang,
  • Meng-qi Zhang,
  • Ying-ying Chen,
  • Jin-yue Sun,
  • Chao Liu

摘要

URAT1 represents a critical therapeutic target for the treatment of hyperuricemia. However, current URAT1 inhibitors are limited by high toxicity and adverse effects, underscoring the urgent need to develop safe and effective therapeutic agents. In this study, nine novel nuciferine derivatives were synthesized by modifying the N7-position substituent to enhance URAT1 inhibitory activity. CCK-8 assays revealed that most compounds exhibited no significant cytotoxicity in HK-2 cells at concentrations up to 60 μM, supporting their suitability for further investigation. Western blot analysis demonstrated that the majority of derivatives downregulated URAT1 protein expression in HK-2 cells, with compound 3-4 exhibiting the most potent inhibition, approaching the efficacy of benzbromarone. Structure-activity relationship (SAR) studies indicated that sulfonyl substituents improved URAT1 inhibition, while aromatic amides reduced activity. Molecular docking showed that 3-4 formed stronger interactions with URAT1 and had higher binding affinity (-6.794 kcal/mol). Molecular dynamics simulations showed that 3-4 formed a stable complex with URAT1. ADME analysis confirmed 3-4 complied with Lipinski’s Rule of Five, featuring balanced lipophilicity and favorable pharmacokinetic properties. These results underscore the N7-position as a key modifiable site for developing nuciferine-based anti-hyperuricemic agents with improved efficacy.