N-substituted arylhydroxamic acids as acetylcholinesterase reactivators.

Area of Science:

• Medicinal Chemistry
• Toxicology
• Neuroscience

Background:

• Acute organophosphorus (OP) poisoning requires versatile antidotes for both central and peripheral nervous system injuries.
• Current treatments necessitate improved medical countermeasures against OP toxicants.

Purpose of the Study:

• To synthesize and evaluate novel benzhydroxamic and salicylhydroxamic acid derivatives as potential OP poisoning antidotes.
• To assess the physicochemical properties, enzyme reactivation capacity, and safety profile of these compounds.

Main Methods:

• Synthesis of N-H, N-methyl, N-butyl, and N-phenyl derivatives of benzhydroxamic and salicylhydroxamic acids.
• In silico prediction of hydrophobicity (log P) and blood-brain barrier (BBB) penetration (PAMPA).
• In vitro assessment of human acetylcholinesterase (HssAChE) reactivation, mammalian cell viability (CHO-K1), and biodegradability (OECD 301D).
• Molecular docking studies to analyze binding to the AChE active site.

Main Results:

• N-butyl derivatives exhibited a balanced combination of properties, with N-butylsalicylhydroxamic acid being the most promising.
• Compounds showed modest HssAChE reactivation capacity against GB, VX, and paraoxon.
• Methyl substitution (N-Me) enhanced reactivation capacity across tested OP substrates.

Conclusions:

• The study identified N-butylsalicylhydroxamic acid as a lead compound for developing new OP poisoning antidotes.
• Structure-activity relationships suggest that modifications can optimize antidote properties.
• These findings contribute to the selection of perspective structures for medical countermeasures against OP toxicants.