Novel tacrine-pyridinium hybrid reactivators of organophosphorus-inhibited acetylcholinesterase: Synthesis, molecular docking, and in vitro reactivation study
Kim, Jinwoo
(Division of Bio and Drug Discovery, Korea Research Institute of Chemical Technology)
,
Malpani, Yashwardhan R.
(Division of Bio and Drug Discovery, Korea Research Institute of Chemical Technology)
,
Lee, Jooyun
(Division of Bio and Drug Discovery, Korea Research Institute of Chemical Technology)
,
Shin, Jin Soo
(Division of Bio and Drug Discovery, Korea Research Institute of Chemical Technology)
,
Han, Soo Bong
(Division of Bio and Drug Discovery, Korea Research Institute of Chemical Technology)
,
Jung, Young-Sik
(Division of Bio and Drug Discovery, Korea Research Institute of Chemical Technology)
Abstract First-line medical treatment against nerve agents consists of co-administration of anticholinergic agents and oxime reactivators, which reactivate inhibited AChE. Pralidoxime, a commonly used oxime reactivator, is effective against some nerve agents but not against others; thus, new oxime ...
Abstract First-line medical treatment against nerve agents consists of co-administration of anticholinergic agents and oxime reactivators, which reactivate inhibited AChE. Pralidoxime, a commonly used oxime reactivator, is effective against some nerve agents but not against others; thus, new oxime reactivators are needed. Novel tacrine-pyridinium hybrid reactivators in which 4-pyridinealdoxime derivatives are connected to tacrine moieties by linear carbon chains of different lengths (C2–C7) were prepared (, 5a–f). Their binding affinities to electric eel AChE were tested because oximes can inhibit free AChE, and the highest AChE activity (95%, 92%, and 90%) was observed at 1 μM concentrations of the oximes (5a, 5b, and 5c, respectively). Based on their inhibitory affinities towards free AChE, 1 μM concentrations of the oxime derivatives (5) were used to examine reactivation of paraoxon-inhibited AChE. Reactivation ability increased as the carbon linker chains lengthened (n = 2–5), and 5c and 5d showed remarkable reactivation ability (41%) compared to that of 2-PAM (16%) and HI-6 (4%) against paraoxon-inhibited electric eel AChE at 1 μM concentrations. Molecular docking simulation showed that the most stable binding free energy was observed in 5c at 73.79 kcal⋅mol−1, and the binding mode of 5c is acceptable for the oxygen atom of oximate to attack the phosphorus atom of paraoxon and reactivate paraoxon-inhibited eel AChE model structure. Highlights Novel tacrine-pyridinium hybrid reactivators were prepared. Binding affinity of compound 5c to electric eel AChE was observed 90% at 1 μM concentration. Compound 5c showed 41% reactivation potency at 1 μM concentration against paraxon inhibited AChE. Molecular modeling predicted that the optimal distance between 5c and paraoxon was 5.02 Å. Graphical abstract [DISPLAY OMISSION]
Abstract First-line medical treatment against nerve agents consists of co-administration of anticholinergic agents and oxime reactivators, which reactivate inhibited AChE. Pralidoxime, a commonly used oxime reactivator, is effective against some nerve agents but not against others; thus, new oxime reactivators are needed. Novel tacrine-pyridinium hybrid reactivators in which 4-pyridinealdoxime derivatives are connected to tacrine moieties by linear carbon chains of different lengths (C2–C7) were prepared (, 5a–f). Their binding affinities to electric eel AChE were tested because oximes can inhibit free AChE, and the highest AChE activity (95%, 92%, and 90%) was observed at 1 μM concentrations of the oximes (5a, 5b, and 5c, respectively). Based on their inhibitory affinities towards free AChE, 1 μM concentrations of the oxime derivatives (5) were used to examine reactivation of paraoxon-inhibited AChE. Reactivation ability increased as the carbon linker chains lengthened (n = 2–5), and 5c and 5d showed remarkable reactivation ability (41%) compared to that of 2-PAM (16%) and HI-6 (4%) against paraoxon-inhibited electric eel AChE at 1 μM concentrations. Molecular docking simulation showed that the most stable binding free energy was observed in 5c at 73.79 kcal⋅mol−1, and the binding mode of 5c is acceptable for the oxygen atom of oximate to attack the phosphorus atom of paraoxon and reactivate paraoxon-inhibited eel AChE model structure. Highlights Novel tacrine-pyridinium hybrid reactivators were prepared. Binding affinity of compound 5c to electric eel AChE was observed 90% at 1 μM concentration. Compound 5c showed 41% reactivation potency at 1 μM concentration against paraxon inhibited AChE. Molecular modeling predicted that the optimal distance between 5c and paraoxon was 5.02 Å. Graphical abstract [DISPLAY OMISSION]
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