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Discovery of soluble epoxide hydrolase inhibitors based on the skeleton of piperine: synthesis, properties, molecular dynamics simulation, and their potentials in acute lung injury
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Juan Zhang1, 2, Xue-Tao Yang3, Min Zhang1, Qi-Meng Zhu1, Da-Hong Yao3, *, Xiao-Chi Ma4, *, Bruce D. Hammock2, *, Cheng-Peng Sun1, *
Acupuncture and Herbal Medicine | 2025, 5(2) : 193 - 204
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Acupuncture and Herbal Medicine | 2025, 5(2): 193-204
• Original Articles •
Discovery of soluble epoxide hydrolase inhibitors based on the skeleton of piperine: synthesis, properties, molecular dynamics simulation, and their potentials in acute lung injury
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Juan Zhang1, 2, Xue-Tao Yang3, Min Zhang1, Qi-Meng Zhu1, Da-Hong Yao3, *, Xiao-Chi Ma4, *, Bruce D. Hammock2, *, Cheng-Peng Sun1, *
Affiliations
  • 1School of Chinese Materia Medica, School of Medical Technology, Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
  • 2Department of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California, Davis, CA, USA
  • 3School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen, China
  • 4Second Affiliated Hospital, Dalian Medical University, Dalian, China
About Author:

Juan Zhang and Xue-Tao Yang contributed equally to this work.

Published: 2025-06-25 doi: 10.1097/HM9.0000000000000148
Outline
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Objective:

Soluble epoxide hydrolase (sEH) emerges as a target of interest for inflammatory diseases. Piperine is a natural amide alkaloid from Piper nigrum and displays an inhibitory effect toward sEH, its chemical structural transformation was carried out in order to obtain a library of sEH inhibitors based on its skeleton.

Methods:

Structural transformation of piperine was carried out by chemical methods, and piperine derivatives were assayed for their sEH potentials. A mouse acute lung injury model was constructed by lipopolysaccharide (LPS). Hematoxylin and eosin (H&E) staining, immunofluorescence staining, Western Blot, and enzyme-linked immunosorbent assay were used for investigating the protective potential of sEH inhibitor 11h.

Results:

Piperine derivatives 11e, 11h, 11j, and 11o showed inhibitory potentials toward sEH with values of half maximal inhibitory concentration (IC50) from 20 to 70 nM. Compound 11h attenuated the pathological course of LPS-mediated acute lung injury (ALI) in vivo. Furthermore, levels of cytokines tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), myeloperoxidase (MPO), and lactate dehydrogenase (LDH) were decreased after administration of 11h. The LPS-mediated inflammation and redox unbalance, including expressions of cyclooxygenase-2 (COX-2), heme oxygenase-1 (HO-1), intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), p-p65/p65, glutamate-cysteine ligase modifier subunit (GCLM), and nuclear factor erythroid-2-related factor 2 (Nrf2), were ameliorated through nuclear factor kappa B (NF-κB) and Nrf2 pathways via enhancing levels of epoxyeicosatrienoic acids (EETs) in LPS-exposed ALI mice after compound 11h treatment. Molecular docking demonstrated that the aromatic unsaturated group of 11h occupied a hydrophobic pocket and its urea group formed three hydrogen bonds with Asp333, Tyr381, and Tyr465, which stabilized the active conformation of the ligand.

Conclusions:

These findings demonstrated that compound 11h may serve as a lead compound for developing sEH inhibitors and treating inflammation related to diseases, such as ALI.

Inflammation  /  Piperine  /  Soluble epoxide hydrolase  /  Structure-activity relationship
Juan Zhang, Xue-Tao Yang, Min Zhang, Qi-Meng Zhu, Da-Hong Yao, Xiao-Chi Ma, Bruce D. Hammock, Cheng-Peng Sun. Discovery of soluble epoxide hydrolase inhibitors based on the skeleton of piperine: synthesis, properties, molecular dynamics simulation, and their potentials in acute lung injury[J]. Acupuncture and Herbal Medicine, 2025 , 5 (2) : 193 -204 . DOI: 10.1097/HM9.0000000000000148
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Funding
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  • National Natural Science Foundation of China(82274069; 82003580)
  • Shenzhen science and technology research and development funds(JCYJ20190808171803553; 2022071718149001)
  • Young Scientific and Technological Talents (Level Two) in Tianjin(QN2023021)
  • Tianjin Education Commission Research Program Project(2024KJ004)
  • Young Elite Scientists Sponsorship Program by China Association of Chinese Medicine(2022-QNRC2-B09)
  • "1 + X" Research Project of the Second Hospital of Dalian Medical University(2024JJ11PT005)
  • Eaglet Plan Project of Tianjin University of Traditional Chinese Medicine(XJS2024101)
Appendix
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Year 2025 volume 5 Issue 2
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Article Info
doi: 10.1097/HM9.0000000000000148
  • Receive Date：2024-01-17
  • Online Date：2026-11-04
  • Published：2025-06-25
Article Data
Affiliations
History
  • Received：2024-01-17
  • Accepted：2025-02-12
Funding
National Natural Science Foundation of China(82274069; 82003580)
Shenzhen science and technology research and development funds(JCYJ20190808171803553; 2022071718149001)
Young Scientific and Technological Talents (Level Two) in Tianjin(QN2023021)
Tianjin Education Commission Research Program Project(2024KJ004)
Young Elite Scientists Sponsorship Program by China Association of Chinese Medicine(2022-QNRC2-B09)
"1 + X" Research Project of the Second Hospital of Dalian Medical University(2024JJ11PT005)
Eaglet Plan Project of Tianjin University of Traditional Chinese Medicine(XJS2024101)
Affiliations
    1School of Chinese Materia Medica, School of Medical Technology, Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
    2Department of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California, Davis, CA, USA
    3School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen, China
    4Second Affiliated Hospital, Dalian Medical University, Dalian, China

Corresponding:

* Da-Hong Yao, E-mail: ;
Xiao-Chi Ma, E-mail: ;
Bruce D. Hammock, E-mail: ;
Cheng-Peng Sun, E-mail: .
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表12种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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