In silico and in vitro studies of two non-imidazole multiple targeting agents at histamine H3 receptors and cholinesterase enzymes

Chem Biol Drug Des. 2020 Feb;95(2):279-290. doi: 10.1111/cbdd.13642. Epub 2019 Nov 12.

Abstract

Recently, multi-target directed ligands have been of research interest for multifactorial disorders such as Alzheimer's disease (AD). Since H3 receptors (H3 Rs) and cholinesterases are involved in pathophysiology of AD, identification of dual-acting compounds capable of improving cholinergic neurotransmission is of importance in AD pharmacotherapy. In the present study, H3 R antagonistic activity combined with anticholinesterase properties of two previously computationally identified lead compounds, that is, compound 3 (6-chloro-N-methyl-N-[3-(4-methylpiperazin-1-yl)propyl]-1H-indole-2-carboxamide) and compound 4 (7-chloro-N-[(1-methylpiperidin-3-yl)methyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxamide), was tested. Moreover, molecular docking and binding free energy calculations were conducted for binding mode and affinity prediction of studied ligands toward cholinesterases. Biological evaluations revealed inhibitory activity of ligands in nanomolar (compound 3: H3 R EC50 = 0.73 nM; compound 4: H3 R EC50 = 31 nM) and micromolar values (compound 3: AChE IC50 = 9.09 µM, BuChE IC50 = 21.10 µM; compound 4: AChE IC50 = 8.40 µM, BuChE IC50 = 4.93 µM) for H3 R antagonism and cholinesterase inhibition, respectively. Binding free energies yielded good consistency with cholinesterase inhibitory profiles. The results of this study can be used for lead optimization where dual inhibitory activity on H3 R and cholinesterases is needed. Such ligands can exert their biological activity in a synergistic manner resulting in higher potency and efficacy.

Keywords: anti-H3R agents; anticholinesterase; histamine H3 receptor; molecular docking; molecular dynamics simulation; multi-target directed ligands.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Cholinesterases / drug effects*
  • Computer Simulation
  • Histamine H3 Antagonists / chemistry
  • Histamine H3 Antagonists / pharmacology*
  • In Vitro Techniques
  • Ligands
  • Receptors, Histamine H3 / drug effects*
  • Structure-Activity Relationship

Substances

  • Cholinesterase Inhibitors
  • Histamine H3 Antagonists
  • Ligands
  • Receptors, Histamine H3
  • Cholinesterases