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

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 (IC 50 ) 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.