ABSTRACT
Monoamine oxidase B (MAO-B) is a promising target for the treatment of neurodegenerative disorders. We report the synthesis and the biological evaluation of halogenated derivatives of 1-aryliden-2-(4-phenylthiazol-2-yl)hydrazines. The fluorinated series shows interesting activity and great selectivity toward the human recombinant MAO-B isoform expressed in baculovirus infected BTI insect cells. The multiple crystal structures alignment of the enzyme highlighted pronounced induced fit (IF) adaptations with respect to bound ligands. Therefore, IF docking (IFD) experiments and molecular dynamic (MD) simulations were carried out to reveal the putative binding mode and to explain the experimentally observed differences in the activity of 1-(aryliden-2-(4-(4-chlorophenyl)thiazol-2-yl)hydrazines. The importance of water molecules within the binding site was also investigated. These are known to play an important role in the binding site cavity and to mediate protein-ligand interactions. Detailed analyses of the trajectories provide insights on the chemical features required for the activity of this scaffold. In particular it was highlighted the importance of fluorine atom interacting with the water close to the cofactor and the influence of steric bulkiness of substituents in the arylidene moiety. Free energy perturbation (FEP) analysis confirmed experimental data. The information we deduced will help to develop novel high-affinity MAO-B inhibitors.
Subject(s)
Hydrazones/chemical synthesis , Hydrazones/pharmacology , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase/metabolism , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Binding Sites , Humans , Hydrazones/chemistry , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Dynamics Simulation , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/pharmacology , Parkinson Disease/drug therapy , Protein Conformation , Structure-Activity Relationship , Tandem Mass Spectrometry , Thiazoles/chemistryABSTRACT
Novel 1-(4-arylthiazol-2-yl)-2-(3-methylcyclohexylidene)hydrazine derivatives have been investigated for their ability to inhibit selectively the activity of the human B isoform of monoamine oxidase. These compounds were obtained as racemates and (R)-enantiomers by a stereoconservative synthetic pattern in high yield and enantiomeric excess. The (S)-enantiomers of the most active derivatives have been separated by enantioselective HPLC. All compounds showed selective activity against hMAO-B with IC(50) ranging between 21.90 and 0.018 microM.
Subject(s)
Cyclohexanes/chemical synthesis , Hydrazines/chemical synthesis , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase/chemistry , Triazoles/chemical synthesis , Chromatography, High Pressure Liquid , Cyclohexanes/chemistry , Cyclohexanes/isolation & purification , Humans , Hydrazines/chemistry , Hydrazines/isolation & purification , Isoenzymes/antagonists & inhibitors , Isoenzymes/chemistry , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/isolation & purification , Stereoisomerism , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/isolation & purificationABSTRACT
A new series of synthetic flavones, thioflavones, and flavanones has been synthesized and evaluated as potential inhibitors of monoamine oxidase isoforms (MAO-A and -B). The most active series is the flavanone one with higher selective inhibitory activity against MAO-B. Some of these flavanones (mainly the most effective) have been separated and tested as single enantiomers. In order to investigate the MAOs recognition of the most active and selective compounds, a molecular modeling study has been performed using available Protein Data Bank (PDB) structures as receptor models for docking experiments.