Novel cinobufagin oxime ether derivatives as potential Na + /K + -ATPase inhibitors: Synthesis, biological screening and molecular docking

Some cinobufagin oxime ether derivatives as potential Na + /K + -ATPase inhibitors were synthesized by following the side chain of istaroxime. These compounds inhibit Na + /K + -ATPase in a dose-dependent manner. Compound 3 c with an oxyethylamine side chain that is the same as that of istaroxime showed the most potent inhibition, which was stronger than compound 3 a with only hydroxyoxime moiety at C-3 and compound 3 b with a methylated hydroxyoxime moiety. Molecular docking was used to explore the binding modes of the target compounds with Na + /K + -ATPase, which suggested that the longer ethyl amine group at C-3 oxime moiety of compound 3 c could make stronger interaction with Na + /K + -ATPase via intermolecular charge-charge and H-bond interaction as compared with other derivatives.