Novel bifunctional hybrid small molecule scavengers for mitigating nerve agents toxicity

• Published in: Chemico-biological interactions Vol. 259; no. Pt B; pp. 187 - 204
• Main Authors: Amitai, Gabriel, Gez, Rellie, Raveh, Lily, Bar-Ner, Nira, Grauer, Ettie, Chapman, Shira
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 25.11.2016
• Subjects: 2-Pyridine aldoxime methyl chloride; 4-Pyridine hydroxamic acid; Acetylcholinesterase; Acetylcholinesterase - blood; Acetylcholinesterase - metabolism; Animals; Antidotes - pharmacology; Benzhydroxamic acid; Bifunctional; Cholinesterase Inhibitors - pharmacology; Cholinesterase Reactivators - pharmacology; Cyclosarin; Detoxification; Guinea pig; Guinea Pigs; Humans; Hydroxamic Acids - chemistry; Inhibitory Concentration 50; Kinetics; Male; Nerve agents; Nerve Agents - toxicity; Neurotoxins - toxicity; Organophosphates; Organophosphates - toxicity; Organophosphorus Compounds - toxicity; Organothiophosphorus Compounds - toxicity; Oxime; Oximes - chemistry; Phosphorylation - drug effects; Rat; Rats, Sprague-Dawley; Sarin; Sarin - poisoning; Scavengers; Small molecule; Small Molecule Libraries - pharmacology; Soman; Time Factors; Toxicity Tests, Acute; BChE; VX; PR; NP; Rat; Oxime; Cyclosarin; Acetylcholinesterase; 4PHA; Organophosphates; Guinea pig; Sarin; Soman; Small molecule; 4-Pyridine hydroxamic acid; Nerve agents; AChE; OP; Scavengers; 2-Pyridine aldoxime methyl chloride; Detoxification; i.m; Benzhydroxamic acid; Bifunctional; NA; 2-PAM; BHA
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2016.04.036

The antidotal treatment of organophosphates (OP) nerve agents (NA) poisoning is based on anticholinergics (e.g. atropine) combined with oxime reactivators (e.g. 2PAM) of acetylcholinesterase (AChE). This treatment is symptomatic and does not degrade the OP. New small-molecule OP scavengers were developed as bifunctional hybrids. Their molecular design was based on combining a nucleophile that directly degrades OP with a moiety that reactivates OP-inhibited AChE. The OP degrading moiety is either benzhydroxamic acid (BHA) or 4-pyridinehydroxamic acid (4PHA) coupled via (CH2)n, (n = 1 or 3) to 2PAM. Three newly synthesized oxime-hydroxamate hybrids: 2PAMPr4PHA, 2PAMMeBHA and 2,4-DiPAMMeBHA were found to detoxify sarin, cyclosarin and soman in solution at 3–10-fold faster rate than 2PAM and to reactivate OP-AChE in vitro. 2PAMPr4PHA displayed 18-fold faster reactivation than 2-PAM of cyclosarin-inhibited HuAChE (kr = 3.6 × 102 vs. 0.2 × 102 M−1min−1, respectively, 37 °C). These hybrids inhibited AChE reversibly, IC50 = 16–48 μM, thereby decreasing the inhibition rates by OPs. The LD50 (im) of 2PAMPr4PHA, 2PAMMeBHA and 2,4DiPAMMeBHA are >568, 508 and >506 μmol/kg in rats and 144, 203 and >506 μmol/kg in guinea pigs. The rate of blood ChE recovery by the hybrids administered either pre- or post-exposure to 0.8xLD50 sarin was comparable or faster than 2PAM. Antidotal efficacy of 2PAMPr4PHA, 2PAMMeBHA and 2,4DiPAMMeBHA administered with atropine, as pre-treatment to sarin in rats (im), yielded protection ratios (PR) 11.6, 11.5 and 4.7, respectively, vs. 5.5 with 2PAM. Post-treatment against various OPs in rats and guinea-pigs yielded PRs higher or similar to that of 2 PAM. Our in vivo data indicates that some hybrids may serve as efficient small molecule scavengers for mitigating the toxicity of OP NAs. •Hybrids of degrading moiety coupled to reactivator were developed as OP scavengers.•The degrading moiety Benzhydroxamic or 4-pyridinehydroxamic acid was linked to 2PAM•Three new hybrids degraded OPs, reactivated OP-AChE and reversibly inhibited AChE.•Pre-treatment with hybrids protected animals against poisoning by nerve agents.