Publication Type:

Journal Article

Source:

Molecules, Volume 25, Issue 22, p.5371 (2020)

URL:

https://pubmed.ncbi.nlm.nih.gov/33212876/

Keywords:

Animals, Carbon-13 Magnetic Resonance Spectroscopy, Cell death, Cell Line, Cell Survival, drug design, kinetics, Mice, Molecular Docking Simulation, Monoamine oxidase, Monoamine Oxidase Inhibitors, Piperazine, Proton Magnetic Resonance Spectroscopy, Pyridazines, Recombinant Proteins

Abstract:

Twelve pyridazinones (-) containing the (2-fluorophenyl) piperazine moiety were designed, synthesized, and evaluated for monoamine oxidase (MAO) -A and -B inhibitory activities. was found to be the most potent MAO-B inhibitor with an IC value of 0.013 µM, followed by (IC = 0.039 µM). Inhibitory potency for MAO-B was more enhanced by bromo substitution () than by bromo substitution (). For substitution, inhibitory potencies for MAO-B were as follows: -Cl () > -N(CH) () > -OCH () > Br () > F () > -CH () > -H (). and efficiently inhibited MAO-A with IC values of 1.57 and 4.19 µM and had the highest selectivity indices (SIs) for MAO-B (120.8 and 107.4, respectively). and were found to be reversible and competitive inhibitors of MAO-B with K values of 0.014 and 0.0071, respectively. Moreover, was less toxic to healthy fibroblast cells (L929) than . Molecular docking simulations with MAO binding sites returned higher docking scores for and with MAO-B than with MAO-A. These results suggest that and are selective, reversible, and competitive inhibitors of MAO-B and should be considered lead candidates for the treatment of neurodegenerative disorders like Alzheimer's disease.

Cite this Research Publication

M. Çeçen, Oh, J. Min, Özdemir, Z., Büyüktuncel, S. Ebru, Uysal, M., Abdelgawad, M. A., Musa, A., Gambacorta, N., Nicolotti, O., Mathew, B., and Kim, H., “Design, Synthesis, and Biological Evaluation of Pyridazinones Containing the (2-Fluorophenyl) Piperazine Moiety as Selective MAO-B Inhibitors.”, Molecules, vol. 25, no. 22, p. 5371, 2020.