A chemical comparison of methanesulfonyl fluoride with organofluorophosphorus ester anticholinesterase compounds

Abstract

The chemical reactivity and physical properties of methanesulfonyl fluoride (MSF) were quantitatively measured for direct comparison with those of isopropyl methylphosphonofluoridate (GB, sarin) and diisopropyl phosphorofluoridate (DFP). The chemistry involved reaction rate constant measurements of MSF hydrolysis and for reactions with phenolic, amine, oxime, hydroxamic acid, phenyl N-hydroxycarbamate, and hydroxylamine compounds and cupric imidazole and bipyridyl complexes. Analogous chemistry with GB and DFP occurred only for the nucleophilic reactions. MSF was substantially less reactive toward interactions involving hydrogen bonding, cupric complex coordination, and quaternary amine formation. Physical characterization included water solubility, vapor pressure, heat of vaporization, solubility parameter, hydrogen bond basicity, UV, IR, and NMR measurements. MSF is a much weaker hydrogen bond acceptor than the phosphorus esters. The hydrogen bond basicity beta-scale measurement provides a key insight to the chemical reactivity divergence of MSF and DFP or GB. Its unexpectedly low value is interpreted that MSF does not possess a site with sufficient basicity to be protonated by strong acid, to enter into hydrogen bonding, or for coordination with the cupric ion.

A randomized phase I study of methanesulfonyl fluoride, an irreversible cholinesterase inhibitor, for the treatment of Alzheimer's disease

“…It was estimated that roughly 1% was excreted in urine which was not surprising given the poor long term stability of MSF in aqueous solution . The vast majority of MSF probably underwent spontaneous hydrolysis to methanesulfonic acid within a few hours at physiological pH (k w = 1 × 10 −4 s −1 ) . The absolute oral bioavailability could not be measured from the present study.…”

“…MSF excretion in urine was detectable up to 8 h after doses of 3.6 mg, until 12 h after 7.2 mg, and up to 24 h after the highest dose of 10.8 mg. A definite conclusion whether MSF excretion in urine was dose dependent was not possible. It was estimated that roughly 1% was excreted in urine which was not surprising given the poor long term stability of MSF in aqueous solution . The vast majority of MSF probably underwent spontaneous hydrolysis to methanesulfonic acid within a few hours at physiological pH (k w = 1 × 10 −4 s −1 ) .…”

Cholinesterase Inhibitor Therapy in Alzheimer’s Disease: The Limits and Tolerability of Irreversible CNS-Selective Acetylcholinesterase Inhibition in Primates

“…No attempt was made in either Experiment One or Two to measure the concentration of MSF or its metabolites in brain, blood, or CSF because MSF undergoes rapid spontaneous hydrolysis to methanesulfonic acid and disappears from blood with a t 1/2 of ~ 2 hours [30, 34]. There appears to be no conventional metabolic processing of MSF.…”

Improving Anti-Neurodegenerative Benefits of Acetylcholinesterase Inhibitors in Alzheimer’s Disease: Are Irreversible Inhibitors the Future?

“…The sulfonyl fluorides, like carbamates (e.g., rivastigmine) and organophosphates [133], react covalently with the essential serine oxygen in the catalytic site of AChE to block the enzyme catalytic mechanism (Figure 1) [113,131,132]. The sulfonyl fluorides, specifically including MSF, do not inhibit neuropathy target enzyme, the hypothesized cause of organophosphate-induced delayed Comparison of brain AChE inhibition produced by reversible inhibitors (donepezil, rivastigmine, and galantamine) to an irreversible inhibitior (methanesulfonyl fluoride).…”

“…MSF has uncommon pharmacokinetics. Even though MSF-induced inhibition of CNS AChE disappears with a half-time of~12 days, the time required for new synthesis, the MSF drug molecule itself is unstable in an aqueous environment such as human blood and undergoes inactivation by in vivo spontaneous hydrolysis to form methanesulfonic acid, an inactive compound, with a half-time of 2.6 h [128,133]. Therefore, MSF administered on a daily schedule like that simulated in Figure 2 produces a pulsatile increment in AChE inhibition that is followed by a drug-free period of~16 h per day during which new synthesis of uninhibited replacement AChE occurs [69].…”