The present armamentarium of commercially available antidotes provides limited protection against the neurological effects of organophosphate exposure. Hence, there is an urgent need to design and develop molecules that can protect and reactivate inhibited-AChE in the central nervous system. Some natural compounds like glucose and certain amino acids (glutamate, the anion of glutamic acid) can easily cross the blood brain barrier although they are highly polar. Glucose is mainly transported by systems like glucose transporter protein type 1 (GLUT1). For this reason, a series of non-quaternary and quaternary glycosylated imidazolium oximes with different alkane linkers have been designed and synthesized. These compounds were evaluated for their in-vitro reactivation ability against pesticide (paraoxon-ethyl and paraoxon-methyl) inhibited-AChE and compared with standards antidote AChE reactivators pralidoxime and obidoxime. Several physicochemical properties including acid dissociation constant (pKa), logP, logD, HBD and HBA, have also been assessed for reported compounds. Out of the synthesized compounds, three have exhibited comparable potency with a standard antidote (pralidoxime).
- MeSH
- acetylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory toxicita MeSH
- Electrophorus metabolismus MeSH
- imidazoly chemická syntéza chemie farmakologie MeSH
- kinetika MeSH
- molekulární struktura MeSH
- oximy chemická syntéza chemie farmakologie MeSH
- pesticidy toxicita MeSH
- reaktivátory cholinesterázy chemická syntéza chemie farmakologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Casualties caused by organophosphorus pesticides are a burden for health systems in developing and poor countries. Such compounds are potent acetylcholinesterase irreversible inhibitors, and share the toxic profile with nerve agents. Pyridinium oximes are the only clinically available antidotes against poisoning by these substances, but their poor penetration into the blood-brain barrier hampers the efficient enzyme reactivation at the central nervous system. In searching for structural factors that may be explored in future SAR studies, we evaluated neutral aryloximes as reactivators for paraoxon-inhibited Electrophorus eel acetylcholinesterase. Our findings may result into lead compounds, useful for development of more active compounds for emergencies and supportive care.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- Electrophorus metabolismus MeSH
- enzymové reaktivátory chemie farmakologie MeSH
- molekulární struktura MeSH
- oximy chemie farmakologie MeSH
- paraoxon toxicita MeSH
- rybí proteiny metabolismus MeSH
- techniky in vitro MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- acetylcholin metabolismus MeSH
- acetylcholinesterasa metabolismus MeSH
- acetylthiocholin metabolismus MeSH
- Electrophorus metabolismus MeSH
- hydrolýza MeSH
- katalýza MeSH
- kinetika MeSH
- koncentrace vodíkových iontů MeSH
- rybí proteiny metabolismus MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
A series of twenty-five novel salicylanilide N-alkylcarbamates were investigated as potential acetylcholinesterase inhibitors. The compounds were tested for their ability to inhibit acetylcholinesterase (AChE) from electric eel (Electrophorus electricus L.). Experimental lipophilicity was determined, and the structure-activity relationships are discussed. The mode of binding in the active site of AChE was investigated by molecular docking. All the discussed compounds expressed significantly higher AChE inhibitory activity than rivastigmine and slightly lower than galanthamine. Disubstitution by chlorine in C'(₃,₄) of the aniline ring and the optimal length of hexyl-undecyl alkyl chains in the carbamate moiety provided the most active AChE inhibitors. Monochlorination in C'(₄) exhibited slightly more effective AChE inhibitors than in C'(₃). Generally it can be stated that compounds with higher lipophilicity showed higher inhibition, and the activity of the compounds is strongly dependent on the length of the N-alkyl chain.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory chemie farmakologie MeSH
- Electrophorus metabolismus MeSH
- fenylkarbamáty metabolismus MeSH
- galantamin metabolismus MeSH
- karbamáty chemie farmakologie MeSH
- katalytická doména MeSH
- molekulární modely MeSH
- salicylanilidy chemie farmakologie MeSH
- simulace molekulového dockingu MeSH
- vazebná místa MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Homological series of 14 achiral derivates and series of five chiral derivates of imidazole were tested in vitro as inhibitors of hydrolysis of acetylcholine using enzyme preparation of acetylcholinesterase from electric eel. The batch stirred reactor at 25 degrees C, pH 8 (phosphate buffer), ionic strength 0.11 M and catalytic activity of the enzyme preparation 0.14 U ml(-1) of the reaction mixture were used. The temporal dependences of actual concentrations of acetylcholine, choline and acetic acid were determined by an original HPLC method. For all used inhibitors, these time dependences conform with the probability of more than 90% to the model of competitive irreversible inhibition. All kinetic constants including k(3) defining the rate of inhibition (0.38-5.3M(-1)s(-1)) and qualified estimation of the absolute acetylcholinesterase concentration in the reaction mixture (40-110 nM) were determined.
