Novel potent pyridoxine-based inhibitors of AChE and BChE, structural analogs of pyridostigmine, with improved in vivo safety profile

Bioorg Med Chem Lett. 2016 Aug 15;26(16):4092-4. doi: 10.1016/j.bmcl.2016.06.070. Epub 2016 Jun 25.

Abstract

We report a novel class of carbamate-type ChE inhibitors, structural analogs of pyridostigmine. A small library of congeneric pyridoxine-based compounds was designed, synthesized and evaluated for AChE and BChE enzymes inhibition in vitro. The most active compounds have potent enzyme inhibiting activity with IC50 values in the range of 0.46-2.1μM (for AChE) and 0.59-8.1μM (for BChE), with moderate selectivity for AChE comparable with that of pyridostigmine and neostigmine. Acute toxicity studies using mice models demonstrated excellent safety profile of the obtained compounds with LD50 in the range of 22-326mg/kg, while pyridostigmine and neostigmine are much more toxic (LD50 3.3 and 0.51mg/kg, respectively). The obtained results pave the way to design of novel potent and safe cholinesterase inhibitors for symptomatic treatment of neuromuscular disorders.

Keywords: Acetylcholinesterase (AChE) inhibitors; Carbamate cholinesterase inhibitors; Neuromuscular disorders treatment; Pyridostigmine analogs; Substituted pyridoxines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / metabolism*
  • Animals
  • Butyrylcholinesterase / chemistry
  • Butyrylcholinesterase / metabolism*
  • Cholinesterase Inhibitors / chemistry*
  • Cholinesterase Inhibitors / metabolism
  • Cholinesterase Inhibitors / toxicity
  • Lethal Dose 50
  • Mice
  • Protein Binding
  • Pyridostigmine Bromide / analogs & derivatives*
  • Pyridostigmine Bromide / metabolism
  • Pyridostigmine Bromide / toxicity
  • Pyridoxine / chemistry*
  • Structure-Activity Relationship
  • Toxicity Tests, Acute

Substances

  • Cholinesterase Inhibitors
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • Pyridoxine
  • Pyridostigmine Bromide