# Ionic and Non-Ionic Counterparts Based on Bis(Uracilyl)Alkane Moiety with Highest Selectivity Towards Acetylcholinesterase for Protection Against Organophosphate Poisoning and Treating Alzheimer’s Disease

## TL;DR

Scientists developed new compounds that selectively block a brain enzyme, showing potential for treating Alzheimer's and protecting against nerve agent poisoning.

## Contribution

The study introduces bisuracils with high selectivity for acetylcholinesterase, offering dual applications in organophosphate poisoning and Alzheimer’s.

## Key findings

- Bisuracils inhibited acetylcholinesterase at nano- and sub-nanomolar concentrations with high selectivity over butyrylcholinesterase.
- Compound 2b protected acetylcholinesterase from paraoxon poisoning in mice at low doses.
- Compound 3c reversed memory loss in mice, suggesting potential for Alzheimer’s treatment.

## Abstract

A series of bisuracils, in which uracil and 3,6-dimethyluracil moieties were bridged with a polymethylene spacer, and the uracil moiety contained a pentamethylene radical with ionic and non-ionic aminobenzyl groups, were synthesised. These bisuracils have been identified as cholinesterase inhibitors with exceptional selectivity for acetylcholinesterase (AChE) over butyrylcholinesterase (BuChE). These bisuracils, which have been identified as highly effective AChE inhibitors, demonstrated activity at nano- and sub-nanomolar concentrations, with exceptional selectivity for AChE over BuChE. In kinetic studies of lead bisuracils 2b and 3c, both compounds exhibited mixed-type inhibition against AChE and BuChE. Additionally, molecular dynamic simulations demonstrated robust and stable interactions of 2b and 3c with the binding sites of their target. Bisuracil 2b showed significant potential for protection of AChE from irreversible inhibition by paraoxon; the most effective dose of 0.01 mg/kg was shown to reduce mortality in paraoxon-poisoned mice. Bisuracil 3c effectively inhibited brain AChE activity, reversing scopolamine-induced amnesia in mice at a dose of 5 mg/kg, which indicates its potential for cognitive enhancement. These findings position ionic bisuracils as promising prophylactics against organophosphate poisoning and non-ionic bisuracils as viable candidates for Alzheimer’s disease therapeutics.