Discovery of multi-target anti-gout agents from Eurycoma longifolia Jack through phenotypic screening and structural
Zhijiao Zhang1, Xiaoyu Shi1, Ting Wu2
1State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P. R. China.
None:
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.
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