Pyrazole[3,4-d]pyridazine derivatives: Molecular docking and explore of acetylcholinesterase and carbonic anhydrase enzymes inhibitors as anticholinergics potentials

Bioorg Chem. 2019 Nov:92:103213. doi: 10.1016/j.bioorg.2019.103213. Epub 2019 Aug 20.

Abstract

Recently, the pyridazine nucleus has been widely studied in the field of particular and new medicinal factors as drugs acting on the cardiovascular system. Additionally, a number of thienopyridazines have been claimed to possess interacting biological macromolecules and pharmacological activities such as NAD(P)H oxidase inhibitor, anticancer, and identified as a novel allosteric modulator of the adenosine A1 receptor. The literature survey demonstrates that coumarin, 1,2-pyrazole benzothiazole, and 1,3- thiazole scaffolds are the most versatile class of molecules. In this study, a series of substituted pyrazole[3,4-d]pyridazine derivatives (2a-n) were prepared, and their structures were characterized by Mass analysis, NMR, and FT-IR. These obtained pyrazole[3,4-d]pyridazine compounds were very good inhibitors of the carbonic anhydrase (hCA I and II) isoenzymes and acetylcholinesterase (AChE) with Ki values in the range of 9.03 ± 3.81-55.42 ± 14.77 nM for hCA I, 18.04 ± 4.55-66.24 ± 19.21 nM for hCA II, and 394.77 ± 68.13-952.93 ± 182.72 nM for AChE, respectively. The possible inhibition mechanism of the best-posed pyrazole[3,4-d]pyridazine and pyrazole-3-carboxylic acid derivatives and their interaction with catalytic active pocket residues were determined based on the calculations.

Keywords: Carbonic anhydrase; Computational studies; Enzyme inhibition; Molecular docking.

MeSH terms

  • Acetylcholinesterase / metabolism
  • Animals
  • Carbonic Anhydrase I / antagonists & inhibitors
  • Carbonic Anhydrase II / antagonists & inhibitors
  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Cholinergic Antagonists / chemical synthesis
  • Cholinergic Antagonists / chemistry
  • Cholinergic Antagonists / pharmacology*
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Electrophorus
  • Humans
  • Molecular Docking Simulation*
  • Molecular Structure
  • Pyridazines / chemical synthesis
  • Pyridazines / chemistry
  • Pyridazines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Carbonic Anhydrase Inhibitors
  • Cholinergic Antagonists
  • Cholinesterase Inhibitors
  • Pyridazines
  • Acetylcholinesterase
  • Carbonic Anhydrase I
  • Carbonic Anhydrase II