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.