Novel thiazolyl-hydrazone derivatives including piperazine ring: synthesis, in vitro evaluation, and molecular docking as selective MAO-A inhibitor.

MAO-A inhibitors are used in the treatment of depression. There are many studies showing that the thiazolyl-hydrazone structure is a pharmacophore structure for the MAO enzyme. In previous studies by our team, activity studies were carried out with thiazolyl-hydrazone derivatives containing pyrrolidine, morpholine, and piperazine. All of them were displayed MAO-A selective inhibition profile. Additionally, derivatives containing piperazine ring were most active. For this purpose, thiazolyl-hydrazone derivatives containing piperazine were synthesized, but this time an active group, formyl group, was added to the piperazine ring as a substituent. Based on this view, new thiazolyl-hydrazone compounds were synthesized, characterized, and screened for their hMAO-A and hMAO-B inhibitory activity by an in vitro fluorometric method. The structure of the compound was tried to be fully elucidated using 2D NMR technique. The compound including 2,4-dimethyl substituent (3i) were found to be the most effective agents in the series against MAO-A enzyme with the IC₅₀ value of 0.080 ± 0.003 µM. The docking study of compound 3i revealed that there is a strong interaction between the active sites of hMAO-A and analyzed compound.