Absolute configuration and biological profile of pyrazoline enantiomers as MAO inhibitory activity
Open Access
Abstract
A new racemic pyrazoline derivative was synthesized and resolved to its enantiomers using analytic and semipreparative high‐pressure liquid chromatography. The absolute configuration of both fractions was established using vibrational circular dichroism. The in vitro monoamine oxidase (MAO) inhibitory profiles were evaluated for the racemate and both enantiomers separately for the two isoforms of the enzyme. The racemic compound and both enantiomers were found to inhibit hMAO‐A selectively and competitively. In particular, the R enantiomer was detected as an exceptionally potent and a selective MAO‐A inhibitor ( K i = 0.85 × 10 −3 ± 0.05 × 10 −3 μM and SI: 2.35 × 10 −5 ), whereas S was determined as poorer compound than R in terms of K i and SI (0.184 ± 0.007 and 0.001). The selectivity of the enantiomers was explained by molecular modeling docking studies based on the PDB enzymatic models of MAO isoforms.Keywords
Funding Information
- International Osteoporosis Foundation
- Bijzonder Onderzoeksfonds UGent
- Türkiye Bilimsel ve Teknolojik Araştırma Kurumu (112T746)
This publication has 57 references indexed in Scilit:
- AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibilityJournal of Computational Chemistry, 2009
- Monoamine oxidase inactivation: From pathophysiology to therapeuticsAdvanced Drug Delivery Reviews, 2008
- Structure of human monoamine oxidase A at 2.2-Å resolution: The control of opening the entry for substrates/inhibitorsProceedings of the National Academy of Sciences, 2008
- Interaction of rat lung SSAO with the novel 1-N-substituted thiocarbamoyl-3-substituted phenyl-5-(2-pyrolyl)-2-pyrazoline derivativesJournal of Neural Transmission, 2007
- Inhibition of Monoamine Oxidase-B by Condensed Pyridazines and Pyrimidines: Effects of Lipophilicity and Structure−Activity RelationshipsJournal of Medicinal Chemistry, 1998
- Synthesis of 1‐(2‐hydroxyphenyl)‐2,4‐imidazolidinedione derivatives through cyclic transformations of ethyl 2‐oxo‐3(2H)‐benzoxazoleacetate derivativesJournal of Heterocyclic Chemistry, 1996
- Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94Journal of Computational Chemistry, 1996
- Monoamine oxidase inhibitors and the cheese effectNeurochemical Research, 1993
- A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye bindingAnalytical Biochemistry, 1976
- Anticonvulsant Activity and Monoamine Oxidase Inhibitory Properties of 1,3,5-Trisubstituted PyrazolinesJournal of Pharmaceutical Sciences, 1974