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. 2018 May 7;23(5):1103.
doi: 10.3390/molecules23051103.

Synthesis, Biological Evaluation, and Docking Studies of Novel Bisquaternary Aldoxime Reactivators on Acetylcholinesterase and Butyrylcholinesterase Inhibited by Paraoxon

Kamil Kuca  1 , Daniel Jun  2   3 , Lucie Junova  4 , Kamil Musilek  5   6 , Martina Hrabinova  7   8 , Jorge Alberto Valle da Silva  9   10 , Teodorico Castro Ramalho  11   12 , Marian Valko  13 , Qinghua Wu  14   15 , Eugenie Nepovimova  16 , Tanos Celmar Costa França  17   18
Affiliations

Synthesis, Biological Evaluation, and Docking Studies of Novel Bisquaternary Aldoxime Reactivators on Acetylcholinesterase and Butyrylcholinesterase Inhibited by Paraoxon

Kamil Kuca et al. Molecules. .

Abstract

Nerve agents and oxon forms of organophosphorus pesticides act as strong irreversible inhibitors of two cholinesterases in the human body: acetylcholinesterase (AChE; EC 3.1.1.7) and butyrylcholinesterase (BChE; EC 3.1.1.8), and are therefore highly toxic compounds. For the recovery of inhibited AChE, antidotes from the group of pyridinium or bispyridinium aldoxime reactivators (pralidoxime, obidoxime, HI-6) are used in combination with anticholinergics and anticonvulsives. Therapeutic efficacy of reactivators (called “oximes”) depends on their chemical structure and also the type of organophosphorus inhibitor. Three novel oximes (K131, K142, K153) with an oxime group in position four of the pyridinium ring were designed and then tested for their potency to reactivate human (Homo sapiens sapiens) AChE (HssACHE) and BChE (HssBChE) inhibited by the pesticide paraoxon (diethyl 4-nitrophenyl phosphate). According to the obtained results, none of the prepared oximes were able to satisfactorily reactivate paraoxon-inhibited cholinesterases. On the contrary, extraordinary activity of obidoxime in the case of paraoxon-inhibited HssAChE reactivation was confirmed. Additional docking studies pointed to possible explanations for these results.

Keywords: acetylcholinesterase; antidote; butyrylcholinesterase; organophosphate; oxime; paraoxon.

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Conflict of interest statement

Authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structures of clinically used AChE reactivators and oxime K117.
Figure 2
Figure 2
Chemical structures of the cholinesterase reactivators synthesized.
Figure 3
Figure 3
Reactivation of POX-inhibited HssAChE and HssBChE by novel bisquaternary aldoxime reactivators.
Figure 4
Figure 4
Best poses of the oximes inside the complex HssAChE/POX. Distances POP − OSer203 and angles Oox − POP − OSer203 are shown in red.
Figure 5
Figure 5
Best poses of the oximes inside the complex HssBChE/POX. Distances POP − OSer203 and angles Oox − POP − OSer203 are shown in red.
Figure 6
Figure 6
Correlation between the percentage of poses at the near attack conformation (NAC) and the percentage of reactivation for the oximes (Ox) for the complex HssAChE/POX.
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