Discovery of novel ketamine‐inspired derivatives as a protective agent against renal ischemic/reperfusion injury in Wistar rats

Renal ischemia-reperfusion (I/R) injury is a limiting factor for the success of renal grafts and is deemed greatly responsible for the mortality. A novel series of ketamine-inspired compounds was synthesized and subjected to NF-ĸB transcriptional inhibitory activity in LPS-stimulated RAW264.7 cells, where entire set of compounds showed mild-to-moderate significant NF-ĸB transcriptional inhibitory activity (IC50 6.53-67.52 µM). Compound 6d showed highest inhibitory activity among the tested series (IC50 2.62 µM) and found more potent as compared to ketamine as standard. The effect of compound 6d was further quantified in I/R injury in Wistar rats, where it dose-dependently improves kidney function of rats with significant amelioration of kidney injury as suggested by histopathologic examination of renal tissues. It further showed reduction in the generation of pro-inflammatory cytokines and improves the antioxidant status of experimental rats. Compound 6d inhibited apoptosis and increases the expression of Bcl2 and decreases Bax, and cleaved caspase-3 level. It further reduces TLR-4 and NF-κB expression in renal cells of rats, with increases in IκB-α level in Western blot analysis as compared to I/R group. In summary, our current study showed the development of a novel class of ketamine-inspired derivatives against renal ischemia/reperfusion injury.