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.
A novel compound derived from natural products effectively lowers uric acid and reduces gout inflammation. This dual-action drug candidate shows promise for improved gout management and enhanced safety.
Area of Science:
- Natural Product Chemistry
- Medicinal Chemistry
- Pharmacology
Background:
- Gout management requires drugs that lower uric acid and reduce inflammation.
- Natural products offer polypharmacological leads for drug discovery.
- Eurycoma longifolia Jack contains bioactive compounds like beta-carboline-1-propionic acid.
Purpose of the Study:
- To design and synthesize novel anti-gout drug candidates inspired by natural products.
- To develop a dual-acting compound targeting both uric acid levels and inflammation.
- To evaluate the efficacy and safety of synthesized derivatives in preclinical gout models.
Main Methods:
- Utilized a dual-target pharmacophore model for drug design.
- Synthesized 64 derivatives based on beta-carboline-1-propionic acid.
- Screened derivatives for uric acid-lowering and anti-inflammatory activities in mouse and rat models.
Main Results:
- Compound 32 demonstrated potent uric acid-lowering activity, comparable to febuxostat.
- Compound 32 inhibited key urate transporters, reducing uric acid levels.
- Compound 32 mitigated NOD-like receptor protein 3 inflammasome-mediated inflammation in acute gouty arthritis.
- Compound 32 exhibited enhanced safety compared to existing gout medications.
Conclusions:
- A natural product-inspired, dual-mechanism drug discovery approach is effective for gout treatment.
- Compound 32 represents a promising therapeutic candidate for gout management.
- Rational polypharmacology offers significant opportunities for developing novel gout therapies.
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