Synthesis, Conformational Analysis, Antioxidant and Enzyme Inhibition Activity, Molecular Docking, and DFT Studies of New Chiral Hydrazide-Hydrazone Derivatives

Abstract

A new series of chiral hydrazide-hydrazone derivatives were synthesized and evaluated their acetylcholinesterase (AChE), butyrylcholinesterase (BChE), tyrosinase and urease inhibition and antioxidant activities. The chemical structures of newly synthesized chiral aryl hydrazide-hydrazone derivatives were clarified using UV-Vis, IR, H-1 and C-13 NMR, and mass spectroscopies. According to NMR data, due to the partial double bond character of the amide C-N bond, two conformational isomers (E and Z) exist in solution. Based on this information, the conformational properties of the synthesized compounds were investigated using temperature-dependent NMR spectroscopy and DFT. The results of DFT studies revealed that E-(C=N)-E((C(O)-N)) conformer is the most stable structure for the synthesized hydrazones. In addition, the enzyme inhibition potentials of the synthesized compounds were evaluated. Among all chiral hydrazide-hydrazones, compound 3b (containing nitro group in the hydrazone part) had the best inhibition profile against AChE, whereas compound 3d was found to be the most active compound against BChE. In addition, compound 3d, which carries a methoxy group in both the benzamide and the hydrazone moiety, attracted attention due to its good activity against all examined enzymes. Furthermore, molecular docking calculations were performed to get insights into the interaction patterns between the synthesized compounds and the selected target protein.