Chemical, In Cellulo, and In Silico Characterization of the Aminocholine Analogs of VG

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Toxicology

Background:

• V-type nerve agents are highly toxic chemical warfare agents that inhibit acetylcholinesterase (AChE), disrupting neurotransmission.
• Previous research synthesized various V-agent analogs, but aminocholine derivatives remained unexplored.

Purpose of the Study:

• To design and synthesize novel phosphorylated aminocholines as VG analogs.
• To evaluate their potential as acetylcholinesterase (AChE) inhibitors and nerve agent mimics.

Main Methods:

• Synthesis of phosphorylated aminocholines.
• Characterization using NMR spectroscopy (1H, 13C, 31P, TOCSY).
• In silico analysis of pharmacological properties and in vitro toxicological investigation using SH-SY5Y cells.

Main Results:

• Synthesized compounds exhibited drug-likeness but failed to inhibit AChE in vitro and in cellulo.
• The aminocholine moiety was identified as a poor leaving group compared to thiocholine.
• Compound P4 uniquely demonstrated an increase in AChE activity.

Conclusions:

• The novel aminocholine analogs are not effective AChE inhibitors.
• These compounds could serve as safer nerve agent mimics for developing countermeasures.
• P4 shows promise as a lead for developing safer nerve agent pretreatment strategies.