Development of Halogenated Pyrazolines as Selective Monoamine Oxidase-B Inhibitors: Deciphering via Molecular Dynamics Approach

Molecules. 2021 May 28;26(11):3264. doi: 10.3390/molecules26113264.

Abstract

Halogens have been reported to play a major role in the inhibition of monoamine oxidase (MAO), relating to diverse cognitive functions of the central nervous system. Pyrazoline/halogenated pyrazolines were investigated for their inhibitory activities against human monoamine oxidase-A and -B. Halogen substitutions on the phenyl ring located at the fifth position of pyrazoline showed potent MAO-B inhibition. Compound 3-(4-ethoxyphenyl)-5-(4-fluorophenyl)-4,5-dihydro-1H-pyrazole (EH7) showed the highest potency against MAO-B with an IC50 value of 0.063 µM. The potencies against MAO-B were increased in the order of -F (in EH7) > -Cl (EH6) > -Br (EH8) > -H (EH1). The residual activities of most compounds for MAO-A were > 50% at 10 µM, except for EH7 and EH8 (IC50 = 8.38 and 4.31 µM, respectively). EH7 showed the highest selectivity index (SI) value of 133.0 for MAO-B, followed by EH6 at > 55.8. EH7 was a reversible and competitive inhibitor of MAO-B in kinetic and reversibility experiments with a Ki value of 0.034 ± 0.0067 µM. The molecular dynamics study documented that EH7 had a good binding affinity and motional movement within the active site with high stability. It was observed by MM-PBSA that the chirality had little effect on the overall binding of EH7 to MAO-B. Thus, EH7 can be employed for the development of lead molecules for the treatment of various neurodegenerative disorders.

Keywords: halogenated pyrazolines; kinetics; molecular dynamics; monoamine oxidase inhibitors; reversibility.

MeSH terms

  • Blood-Brain Barrier / drug effects
  • Catalytic Domain
  • Chemistry, Pharmaceutical / methods
  • Cognition / drug effects
  • Drug Design
  • Halogens / chemistry
  • Humans
  • Inhibitory Concentration 50
  • Kinetics
  • Models, Chemical
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation*
  • Molecular Structure
  • Monoamine Oxidase / metabolism
  • Monoamine Oxidase Inhibitors / chemistry*
  • Motion
  • Principal Component Analysis
  • Protein Binding
  • Pyrazoles / chemistry*
  • Recombinant Proteins / chemistry
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Halogens
  • Monoamine Oxidase Inhibitors
  • Pyrazoles
  • Recombinant Proteins
  • Monoamine Oxidase