Synthesis and molecular modelling of thiadizole based hydrazone derivatives as acetylcholinesterase and butyrylcholinesterase inhibitory activities.

Some novel substituted thiazolylhydrazine derivatives were designed, synthesized and their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes and antioxidant activities were investigated. The structures of the synthesized compounds were determined using different spectroscopic techniques such as 1H-NMR, 13C-NMR, and HRMS. According to the enzyme inhibition results, the synthesized compounds showed selectivity against BuChE enzyme inhibition. Compounds 5e, 5g, 5i and 5j displayed significant BuChE inhibition potencies. Among them, compound 5i was found to be the most effective derivative with an IC50 value of 56.01 ± 0.054 µM. In addition, their antioxidant properties were evaluated in vitro through the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. For compounds 5e, 5g, 5i and 5j in silico molecular docking and 100 ns molecular dynamics simulations studies against the BuChE enzyme were performed to determine possible protein-ligand interactions and stability. DFT-D3 study was performed to stabilize of compounds 5e, 5g, 5i and 5j both in gas and solvent medium and investigated their electronic properties. Of all geometries, that of DMSO is the lowest one.

Design, Synthesis, In Vitro and In Silico Studies of New Thiazolylhydrazine-Piperazine Derivatives as Selective MAO-A Inhibitors.

Monoamine oxidase (MAO) isoenzymes are very important drug targets among neurological disorders. Herein, novel series of thiazolylhydrazine-piperazine derivatives were designed, synthesized and evaluated for their MAO-A and -B inhibitory activity. The structures of the synthesized compounds were assigned using different spectroscopic techniques such as 1H-NMR, 13C-NMR and HRMS. Moreover, the prediction of ADME (Absorption, Distribution, Metabolism, Elimination) parameters for all of the compounds were performed using in silico method. According to the enzyme inhibition results, the synthesized compounds showed the selectivity against MAO-A enzyme inhibition. Compounds 3c, 3d and 3e displayed significant MAO-A inhibition potencies. Among them, compound 3e was found to be the most effective derivative with an IC50 value of 0.057 ± 0.002 µM. Moreover, it was seen that this compound has a more potent inhibition profile than the reference inhibitors moclobemide (IC50 = 6.061 ± 0.262 µM) and clorgiline (IC50 = 0.062 ± 0.002 µM). In addition, the enzyme kinetics were performed for compound 3e and it was determined that this compound had a competitive and reversible inhibition type. Molecular modeling studies aided in the understanding of the interaction modes between this compound and MAO-A. It was found that compound 3e had significant and important binding property.