ABSTRACT
3-Acetyl-2,5-diaryl-2,3-dihydro-1,3,4-oxadiazoles were designed, synthesized, and tested as inhibitors against human monoamine oxidase (MAO) A and B isoforms. Several compounds, obtained as racemates, were identified as selective MAO-B inhibitors. The enantiomers of some derivatives were separated by enantioselective HPLC and tested. The R-enantiomers always showed the highest activity. Docking study and molecular dynamic simulations demonstrated the putative binding mode. We conclude that these 1,3,4-oxadiazoles derivatives are promising reversible and selective MAO-B inhibitors.
Subject(s)
Monoamine Oxidase Inhibitors/chemical synthesis , Oxadiazoles/chemical synthesis , Animals , Cell Line , Drug Design , Humans , Insecta/cytology , Isoenzymes/antagonists & inhibitors , Models, Molecular , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/pharmacology , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Protein Binding , Recombinant Proteins/antagonists & inhibitors , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A direct HPLC enantioseparation of three new chiral oxadiazoline derivatives endowed with potential MAO-B inhibitory activity was accomplished on the immobilised Chiralpak IA chiral stationary phase. Multi-mg amounts of enantiomers with high enantiomeric purity (ee> or =98%) were rapidly collected using pure dichloromethane as eluent. The absolute configuration and chiroptical properties of the enantiomers isolated at semipreparative scale were exhaustively determined.
Subject(s)
Amylose/chemistry , Chromatography, High Pressure Liquid/methods , Monoamine Oxidase Inhibitors/isolation & purification , Monoamine Oxidase/metabolism , Drug Evaluation, Preclinical , Monoamine Oxidase Inhibitors/chemistry , Oxadiazoles/chemistry , Oxadiazoles/isolation & purification , StereoisomerismABSTRACT
Two series of 2,5-diaryl-1,3,4-oxadiazolines have been studied by multinuclear magnetic resonance and density functional theory calculations. A full NMR spectroscopic characterization has been performed and excellent remote Hammett correlations (sigma(p) or sigma(p)+) have been found for para substitution in the two aryl rings through at least 11 bonds, notwithstanding the presence in the path of atoms that should act as insulators and a lack of correlation for some of the intermediate atoms. The computational investigation on the electronic delocalization, performed with the ACID (anisotropy of the induced current density) method, reveals indeed that electrons are delocalized in almost the entire molecule despite the presence of the insulators.
