Design, Synthesis, and Evaluation of Kirenol Derivatives as MMP-8 Inhibitors with Anti-inflammatory Activity

The diterpene kirenol has notable biological activity. In this study, molecular docking software (Discovery Studio) was adopted to investigate the anti-inflammatory and antioxidant properties of kirenol. Twenty-nine kirenol derivatives were synthesized based on the molecular docking outcomes. Cytotoxicity analyses of the kirenol derivatives were performed in Raw264.7 macrophages using the CCK-8 assay, and nitric oxide (NO) concentrations were determined using the Griess assay. The DCFH-DA approach identified the general pattern of reactive oxygen species (ROS) fluctuations. The mitochondrial mass and morphology were detected using the Mito-Tracker Red fluorescent probe. Preliminary bioassay tests indicated that the concentration of NO was substantially reduced by certain derivatives. Moreover, these derivatives inhibited LPS-induced ROS generation, and one of them exhibited a further reducing ROS generation and pro-inflammatory response by suppressing excessive mitochondrial fission. These findings suggest that this particular derivative may be a promising natural compound for combating oxidative inflammatory diseases.