Aim: To synthesize and evaluate the fused heterocyclic imidazo[1,2-a]pyridine based
oxime as a reactivator against paraoxon inhibited acetylcholinesterase.
Background: Organophosphorus compounds (OPs) include parathion, malathion, chlorpyrifos,
monocrotophos, and diazinon, which are commonly used in agriculture for enhancing agricultural
productivity via killing crop-damaging pests. However, people may get exposed to OPs pesticides
unintentionally/intentionally via ingestion, inhalation, or dermal. The current treatment regimen includes
reactivator such as mono or bis-pyridinium oximes along with anticholinergic and anticonvulsant
drugs that are recommended for the treatment of OP poisoning. Unfortunately, the drawback of
the existing reactivator is the permanent charge present on the pyridinium, making them inefficient to
cross the blood-brain barrier (BBB) and reactivate OP-inhibited central nervous system (CNS) acetylcholinesterase.
Therefore, there is a need of a reactivator that could cross the BBB and reactivate
the OP inhibited acetylcholinesterase.
Objective: The objectives of the study were synthesis, molecular docking, BSA binding, and in-vitro
estimation of oximes of various substituted imidazo [1,2-a]pyridine against paraoxon inhibited acetylcholinesterase.
Method: The reactivators were synthesized in three steps and characterized using various spectroscopic
techniques. The molecular docking study was performed on 2WHP and 3ZLV PDB using the
Glide-XP software. The acid dissociation constant (pKa) of oximes was calculated experimentally,
and the drug-likeness properties of the oximes were calculated in silico using Molinspiration and
Swiss ADME software. The binding of oximes with bovine serum albumin (BSA) was also investigated
using a Fluorescence spectrophotometer. The reactivation potential of the oximes was determined
by in vitro enzymatic assay.
Result: The In-silico study inferred that the synthesized molecules fulfilled the parameters required
for a successful CNS drug candidate. Furthermore, in-vitro enzymatic assay indicated reasonable
reactivation potential of the oximes against paraoxon-inhibited AChE. The binding of oximes with
bovine serum albumin (BSA) revealed that there was a static quenching of intrinsic fluorescence of
BSA by the oxime. The binding constant value and number of binding sites were found to be 0.24 x
104 mol-1 and 1, respectively.
Conclusion: The results of the study concluded that this scaffold could be used for further designing
of more efficient uncharged reactivators.