Discovery of derivatives from Spartina alterniflora-sourced moiety as xanthine oxidase inhibitors to lower uric acid. (1st October 2022)

• Record Type: Journal Article
• Authors: Yang, Yu-Shun; Wang, Bin; Zhou, Kang-Min; Liu, Junzhong; Jiao, Qin-Cai; Qin, Pei
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 73(2022)
• Publication Date: 2022-10-01
• Subjects: Spartina alterniflora -- Xanthine oxidase inhibition -- Lowering uric acid -- Potential agent; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.128907
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Four sub-series of hit compounds, Spartinin F1-F20, sharing the Spartina alterniflora -sourced ferulic acid backbone, were synthesized and evaluated on inhibiting xanthine oxidase and lowering uric acid level. The top hits Spartinin F2 and Spartinin F19 exhibited higher inhibitory potential than the positive control allopurinol. Spartinin F2 inferred potential efficiency in lowering the serum uric acid level and was beneficial for other serum indexes. The bioavailability of Spartinin F2 was 63.71%. The molecular docking simulation indicated that except for retaining the hydrogen bonds with the key residues such as THR 1010 and LYS 771, the introduction of the π-sulfur interactions via the sulfonate might also be beneficial for developing more potent XO inhibitors. Highlights: Twenty Spartina alterniflora -sourced ferulic acid derivatives developed as xanthine oxidase inhibitors. The top hit Spartinin F2 showed potent inhibitory activity for xanthine oxidase. Spartinin F2 could lower the serum uric acid level of hyperuricemic model mice and profit on other serum indexes. Preliminary pharmacokinetics and molecular docking simulation inferred modification orientations. Abstract: In this work, hit compounds Spartinin F1-F20 sharing the Spartina alterniflora -sourced ferulic acid backbone were synthesized and evaluated on inhibiting xanthine oxidase and lowering uric acid level. The top hit Spartinin F2 exhibited inhibition percentages at 10 μM dosage as high as 84.48 (higher than that of the positive control allopurinol) and low cyto-toxicity. Spartinin F2 inferred potential efficiency in lowering the serum UA level (from 631.6 μM to 295.0 μM), which was comparable with allopurinol (to 309.2 μM). Spartinin F2 was also beneficial for other serum indexes. The bioavailability of Spartinin F2 was 63.71% from the preliminary pharmacokinetics test and the molecular docking simulation indicated that except for retaining the hydrogen bonds with the key residues such as THR 1010 and LYS 771, the introduction of the π-sulfur interactions via the sulfonate might also be beneficial for developing more potent XO inhibitors.