Design, Synthesis, and Biological Evaluation of Pyridazinones Containing the (2-Fluorophenyl) Piperazine Moiety as Selective MAO-B Inhibitors

• Published in: Molecules (Basel, Switzerland) Switzerland), 2020-11, Vol.25 (22), p.5371
• Main Authors: Çeçen, Muhammed, Oh, Jong Min, Özdemir, Zeynep, Büyüktuncel, Saliha Ebru, Uysal, Mehtap, Abdelgawad, Mohamed A, Musa, Arafa, Gambacorta, Nicola, Nicolotti, Orazio, Mathew, Bijo, Kim, Hoon
• Format: Article
• Language: English
• Subjects: ADME; Alzheimer's disease; Amine oxidase (flavin-containing); Animals; Carbon-13 Magnetic Resonance Spectroscopy; Cell Death - drug effects; Cell Line; Cell Survival - drug effects; Chlorine; Cytotoxicity; Drug Design; Enzymes; Fluorine; Hemodialysis; Hydrogen bonds; Inhibitors; Kinetics; Medical treatment; Mice; Molecular docking; Molecular Docking Simulation; monoamine oxidase; Monoamine Oxidase - metabolism; Monoamine Oxidase Inhibitors - chemical synthesis; Monoamine Oxidase Inhibitors - chemistry; Monoamine Oxidase Inhibitors - pharmacology; Piperazine; Piperazine - chemical synthesis; Piperazine - chemistry; Piperazine - pharmacology; Proton Magnetic Resonance Spectroscopy; Pyridazines - chemical synthesis; Pyridazines - chemistry; Pyridazines - pharmacology; pyridazinone; Recombinant Proteins - metabolism; reversibility; Selectivity; Simulation; Substitutes
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25225371

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.