Nejvíce citovaný článek - PubMed ID 28418831
The Evaluation of Benefit of Newly Prepared Reversible Inhibitors of Acetylcholinesterase and Commonly Used Pyridostigmine as Pharmacological Pretreatment of Soman-Poisoned Mice
BACKGROUND: Intoxication by nerve agents could be prevented by using small acetylcholinesterase inhibitors (eg, pyridostigmine) for potentially exposed personnel. However, the serious side effects of currently used drugs led to research of novel potent molecules for prophylaxis of organophosphorus intoxication. METHODS: The molecular design, molecular docking, chemical synthesis, in vitro methods (enzyme inhibition, cytotoxicity, and nicotinic receptors modulation), and in vivo methods (acute toxicity and prophylactic effect) were used to study bispyridinium, bisquinolinium, bisisoquinolinium, and pyridinium-quinolinium/isoquinolinium molecules presented in this study. RESULTS: The studied molecules showed non-competitive inhibitory ability towards human acetylcholinesterase in vitro that was further confirmed by molecular modelling studies. Several compounds were selected for further studies. First, their cytotoxicity, nicotinic receptors modulation, and acute toxicity (lethal dose for 50% of laboratory animals [LD50]; mice and rats) were tested to evaluate their safety with promising results. Furthermore, their blood levels were measured to select the appropriate time for prophylactic administration. Finally, the protective ratio of selected compounds against soman-induced toxicity was determined when selected compounds were found similarly potent or only slightly better to standard pyridostigmine. CONCLUSION: The presented small bisquaternary molecules did not show overall benefit in prophylaxis of soman-induced in vivo toxicity.
- Klíčová slova
- AChE inhibitors, nerve agents, pre-treatment, prophylaxis, soman, toxicity,
- MeSH
- acetylcholinesterasa metabolismus MeSH
- buněčné linie MeSH
- cholinesterasové inhibitory chemie farmakologie MeSH
- HeLa buňky MeSH
- knihovny malých molekul chemie farmakologie MeSH
- lidé MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- nervová bojová látka škodlivé účinky MeSH
- soman škodlivé účinky MeSH
- viabilita buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- acetylcholinesterasa MeSH
- cholinesterasové inhibitory MeSH
- knihovny malých molekul MeSH
- nervová bojová látka MeSH
- soman MeSH
