Synthesis of 1,8-cineole derivatives and evaluation of their cytoprotective effects against cisplatin-induced HK-2 cell injury.

This study aimed to discover novel lead compounds for acute kidney injury (AKI) treatment by rationally designing and synthesizing 18 derivatives through structural modifications of 1,8-cineole (c0), a nephroprotective natural product. Initial in vitro screening identified derivative 3c-2 as the most promising candidate. Subsequent evaluations in cisplatin-injured HK-2 cells demonstrated that 3c-2 effectively attenuated cisplatin-induced oxidative stress by reducing reactive oxygen species (ROS) and malondialdehyde (MDA) generation, and enhancing superoxide dismutase (SOD) activity. Comprehensive evaluations combining mitochondrial membrane potential (MMP) measurements and flow cytometry-based apoptosis assays consistently demonstrated that compound 3c-2 possessed a significant inhibitory effect on apoptosis and was effective in attenuating cisplatin-induced cytotoxicity in HK-2 renal tubular epithelial cells. Molecular docking and dynamics simulations indicated stable binding between 3c-2 and PI3K, a key regulator of oxidative stress and apoptosis pathways, suggesting PI3K as the potential therapeutic target of 3c-2.