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Peer-reviewedCC BY 4.0Pharmaceutical Biology

Discovery of potent anti-inflammatory flavonoid-sesquiterpenoid hybrids from Syzygium simile: Structure–activity relationships and nanomolar inhibition of human neutrophil activation

  • Yu-Chun Lin1
  • Ho-Cheng Wu1,2
  • Tsong-Long Hwang3
  • Yueh-Hsiung Kuo4,5
  • Chu-Hung Lin6
  • Horng-Huey Ko1,2,7,8
  • Hsun-Shuo Chang1,2,7
8 affiliations
  1. 1School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
  2. 2Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
  3. 3Graduate Institute of Health Industry Technology and Center for Drug Research and Development, Chang Gung University of Science and Technology, Taoyuan, Taiwan
  4. 4Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
  5. 5Department of Biotechnology, Asia University, Taichung, Taiwan
  6. 6Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan
  7. 7Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
  8. 8Department of Pharmacy, Kaohsiung Municipal Siaogang Hospital, Kaohsiung, Taiwan
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Abstract

Context: Current anti-inflammatory drugs often cause significant adverse effects, underscoring the need for safer alternatives. Natural products with rare and distinctive scaffolds represent a promising source of leads for discovering new anti-inflammatory agents.

Objective: This study aimed to find anti-inflammatory flavonoid-sesquiterpenoid hybrids from Syzygium simile (Myrtaceae), and to clarify the structural-activity relationship underlying their inhibition of biomarkers in activated human neutrophils.

Materials and methods: A range of chromatographic techniques was sequentially applied to isolate pure compounds, the structures of which were elucidated by spectroscopic and spectrometric analyses. Anti-inflammatory activities were evaluated in fMLP/CB-induced human neutrophils by measuring inhibitory effects on superoxide anion generation and elastase release.

Results: Twenty-two flavonoid-sesquiterpenoid hybrids, including thirteen previously undescribed structures, were isolated from S. simile leaves, comprising five flavonoid scaffolds (types I–V) and five sesquiterpenoid moieties (germacrene-, cubebene-, oplopene-, cadinene-, and copaene-types) generated via distinctive electron transfer-mediated biosynthesis. Most compounds potently inhibited superoxide anion generation and elastase release, with IC50 values up to 32-fold lower than that of the positive control, without exhibiting cytotoxicity.

Discussion and Conclusion: Structure-activity relationship analysis revealed that the combination of a type I flavonoid and a germacrene-type sesquiterpenoid skeleton, integrated through an rA-type ring fusion, represents the optimal pharmacophore. The lead compound, simisyzygin C (3), achieved nanomolar potency with IC50 values of 0.04 μM (superoxide anion) and 0.16 μM (elastase release). These findings identify flavonoid-sesquiterpenoid hybrids as a structurally distinctive class of anti-inflammatory natural products, providing a structural basis for lead optimization.

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Cite

BibTeXRIS
BibTeX
@article{lin2026discovery,
  title = {{Discovery of potent anti-inflammatory flavonoid-sesquiterpenoid hybrids from Syzygium simile: Structure–activity relationships and nanomolar inhibition of human neutrophil activation}},
  author = {Yu-Chun Lin and Ho-Cheng Wu and Tsong-Long Hwang and Yueh-Hsiung Kuo and Chu-Hung Lin and Horng-Huey Ko and Hsun-Shuo Chang},
  journal = {Pharmaceutical Biology},
  year = {2026},
  month = oct,
  doi = {10.1080/13880209.2026.2746239},
  url = {https://doi.org/10.1080/13880209.2026.2746239},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Discovery of potent anti-inflammatory flavonoid-sesquiterpenoid hybrids from Syzygium simile: Structure–activity relationships and nanomolar inhibition of human neutrophil activation
AU  - Yu-Chun Lin
AU  - Ho-Cheng Wu
AU  - Tsong-Long Hwang
AU  - Yueh-Hsiung Kuo
AU  - Chu-Hung Lin
AU  - Horng-Huey Ko
AU  - Hsun-Shuo Chang
PY  - 2026
DA  - 2026/10/28
JO  - Pharmaceutical Biology
DO  - 10.1080/13880209.2026.2746239
UR  - https://doi.org/10.1080/13880209.2026.2746239
AB  - Context: Current anti-inflammatory drugs often cause significant adverse effects, underscoring the need for safer alternatives. Natural products with rare and distinctive scaffolds represent a promising source of leads for discovering new anti-inflammatory agents.  Objective: This study aimed to find anti-inflammatory flavonoid-sesquiterpenoid hybrids from Syzygium simile (Myrtaceae), and to clarify the structural-activity relationship underlying their inhibition of biomarkers in activated human neutrophils.  Materials and methods: A range of chromatographic techniques was sequentially applied to isolate pure compounds, the structures of which were elucidated by spectroscopic and spectrometric analyses. Anti-inflammatory activities were evaluated in fMLP/CB-induced human neutrophils by measuring inhibitory effects on superoxide anion generation and elastase release.  Results: Twenty-two flavonoid-sesquiterpenoid hybrids, including thirteen previously undescribed structures, were isolated from S. simile leaves, comprising five flavonoid scaffolds (types I–V) and five sesquiterpenoid moieties (germacrene-, cubebene-, oplopene-, cadinene-, and copaene-types) generated via distinctive electron transfer-mediated biosynthesis. Most compounds potently inhibited superoxide anion generation and elastase release, with IC50 values up to 32-fold lower than that of the positive control, without exhibiting cytotoxicity.  Discussion and Conclusion: Structure-activity relationship analysis revealed that the combination of a type I flavonoid and a germacrene-type sesquiterpenoid skeleton, integrated through an rA-type ring fusion, represents the optimal pharmacophore. The lead compound, simisyzygin C (3), achieved nanomolar potency with IC50 values of 0.04 μM (superoxide anion) and 0.16 μM (elastase release). These findings identify flavonoid-sesquiterpenoid hybrids as a structurally distinctive class of anti-inflammatory natural products, providing a structural basis for lead optimization.
SN  - 1388-0209
SN  - 1744-5116
ER  -