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<p>Developing anti-gout medications that simultaneously reduce uric acid and exert anti-inflammatory effects represents a critical breakthrough for managing gout progression. Natural products with polypharmacological properties offer promising leads for drug discovery. In this study, <i>β-</i>carboline-1-propionic acid, a bioactive constituent of <i>Eurycoma longifolia</i> Jack, served as the starting point for drug design. Guided by a dual-target pharmacophore model, we design and synthesize 64 derivatives. Through systematic screening, <b>32</b> emerges as a drug candidate, demonstrating potent uric acid-lowering activity in male hyperuricemia mouse models (efficacy comparable to febuxostat and superior to lesinurad and benzbromarone) by inhibiting key urate transporters. In a male rat model of acute gouty arthritis, <b>32</b> mitigates NOD-like receptor protein 3 inflammasome-mediated inflammation. Notably, <b>32</b> exhibits enhanced safety compared to control drugs. This study exemplifies a natural product-inspired, dual-mechanism drug discovery approach, showcasing the potential of a rational polypharmacology and thus offering therapeutic opportunities for gout management.</p>

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Discovery of multi-target anti-gout agents from Eurycoma longifolia Jack through phenotypic screening and structural optimization

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月12日

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  • Zhijiao Zhang,
  • Xiaoyu Shi,
  • Ting Wu,
  • Zhuhan He,
  • Ruipeng Liang,
  • Wenjie Ye,
  • Zhenkun Wu,
  • Hui Liao,
  • Fengxin Zheng,
  • Qian Yang,
  • Zean Zhao,
  • Yongjun Chen,
  • Zhen Gao,
  • Shuo Wang,
  • Mei Wang,
  • Zhenqian Wang,
  • Danhui Qi,
  • Mingyu Yang,
  • Shujing Xu,
  • Youzhao Wang,
  • Tong Zhao,
  • Javier Egea,
  • Xinyong Liu,
  • Jianxin Pang,
  • Fan Yi,
  • Peng Zhan

摘要

Developing anti-gout medications that simultaneously reduce uric acid and exert anti-inflammatory effects represents a critical breakthrough for managing gout progression. Natural products with polypharmacological properties offer promising leads for drug discovery. In this study, β-carboline-1-propionic acid, a bioactive constituent of Eurycoma longifolia Jack, served as the starting point for drug design. Guided by a dual-target pharmacophore model, we design and synthesize 64 derivatives. Through systematic screening, 32 emerges as a drug candidate, demonstrating potent uric acid-lowering activity in male hyperuricemia mouse models (efficacy comparable to febuxostat and superior to lesinurad and benzbromarone) by inhibiting key urate transporters. In a male rat model of acute gouty arthritis, 32 mitigates NOD-like receptor protein 3 inflammasome-mediated inflammation. Notably, 32 exhibits enhanced safety compared to control drugs. This study exemplifies a natural product-inspired, dual-mechanism drug discovery approach, showcasing the potential of a rational polypharmacology and thus offering therapeutic opportunities for gout management.