Discovery of soluble epoxide hydrolase inhibitors based on the skeleton of piperine: synthesis, properties, molecular dynamics simulation, and their potentials in acute lung injury

Abstract

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.

Keywords

Inflammation / Piperine / Soluble epoxide hydrolase / Structure-activity relationship

Conflict of interest statement

The authors declare no conflict of interest.

Funding

This work was supported by the National Natural Science Foundation of China (82274069 and 82003580), Shenzhen science and technology research and development funds (JCYJ20190808171803553 and 2022071718149001), Young Scientific and Technological Talents (Level Two) in Tianjin (QN20230212), 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), and Eaglet Plan Project of Tianjin University of Traditional Chinese Medicine (XJS2024101).

Author contributions

Da-Hong Yao, Xiao-Chi Ma, Bruce D. Hammock, and Cheng-Peng Sun designed the research. Juan Zhang and Xue-Tao Yang performed experiments, analyzed data, wrote, and revised the manuscript. Min Zhang and Qi-Meng Zhu analyzed the data. All authors read and approved the manuscript.

Ethical approval of studies and informed consent

Not applicable.

Acknowledgments

None.

Data availability

All relevant data are within the manuscript.

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