Novel Semisynthetic Derivative of Dehydrozingerone (DHZ‐15) Modulates Lipopolysaccharide‐Stimulated Macrophages by Targeting the NF‐κB/p65 Pathway and In Vivo Evaluation in a Sepsis BALB/c Model

Natural products and their semisynthetic derivatives possess tremendous medicinal properties and have the potential to modulate the immune system, providing new therapeutic options for drug development. In this study, we evaluated Dehydrozingerone‐15, a novel dehydrozingerone derivative, for its anti‐inflammatory and antioxidant properties through standardised in vitro and in vivo approaches. Dehydrozingerone‐15 suppressed the stimulatory effect of LPS in RAW 264.7 cells by reducing the secretion of interleukin‐6 (IL‐6), tumour necrosis factor‐alpha (TNF‐α), interleukin‐1 beta (IL‐1β), interleukin‐2 (IL‐2) and nitric oxide. Western blot analysis at the mechanistic level showed a reduced expression level of nitric oxide synthase (iNOS), IκB kinase beta (Ikk‐β) and nuclear factor kappa‐B (NF‐κB/p65). Confocal microscopy studies further demonstrated that Dehydrozingerone‐15 reduced the expression of NF‐κB/p65 markedly. In the in vivo LPS‐induced sepsis model, Dehydrozingerone‐15 administration reduced TNF‐α and IL‐6 expression and protected vital organs (lungs, kidneys, and liver) from acute inflammation. The anti‐inflammatory potential of Dehydrozingerone‐15 was further validated in leukocyte migration induced by carrageenan and vascular permeability triggered by acetic acid assays, both of which showed significant inhibition. Pharmacokinetic analysis revealed that Dehydrozingerone‐15 was rapidly absorbed in BALB/c mice, reaching a C max of 10 349 ng/mL at 0.25 h. The total drug exposure (AUC 0–α ) was 13 862 ng.h/mL, indicating sustained exposure, with high tissue distribution (20 L/kg) and moderate clearance. Additionally, toxicological evaluation at doses up to 2000 mg/kg body weight showed no significant alterations in haematological parameters compared with the vehicle control. Furthermore, based on a comparative evaluation of in vitro and in vivo results, Dehydrozingerone‐15, relative to its parent molecule, demonstrates significant therapeutic potential with high efficacy against inflammation and oxidative stress.