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. 2020 Dec;35(1):478-488.
doi: 10.1080/14756366.2019.1710501.

Synthesis, in vitro screening and molecular docking of isoquinolinium-5-carbaldoximes as acetylcholinesterase and butyrylcholinesterase reactivators

David Malinak  1   2 , Rafael Dolezal  1   2 , Vendula Hepnarova  2   3 , Miroslava Hozova  2 , Rudolf Andrys  1 , Petr Bzonek  1   3 , Veronika Racakova  4 , Jan Korabecny  2   3 , Lukas Gorecki  2 , Eva Mezeiova  2 , Miroslav Psotka  1   2 , Daniel Jun  2   3 , Kamil Kuca  1   2 , Kamil Musilek  1   2
Affiliations

Synthesis, in vitro screening and molecular docking of isoquinolinium-5-carbaldoximes as acetylcholinesterase and butyrylcholinesterase reactivators

David Malinak et al. J Enzyme Inhib Med Chem. 2020 Dec.

Abstract

The series of symmetrical and unsymmetrical isoquinolinium-5-carbaldoximes was designed and prepared for cholinesterase reactivation purposes. The novel compounds were evaluated for intrinsic acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) inhibition, when the majority of novel compounds resulted with high inhibition of both enzymes and only weak inhibitors were selected for reactivation experiments on human AChE or BChE inhibited by sarin, VX, or paraoxon. The AChE reactivation for all used organophosphates was found negligible if compared to the reactivation ability of obidoxime. Importantly, two compounds were found to reactivate BChE inhibited by sarin or VX better to obidoxime at human attainable concentration. One compound resulted as better reactivator of NEMP (VX surrogate)-inhibited BChE than obidoxime. The in vitro results were further rationalized by molecular docking studies showing future directions on designing potent BChE reactivators.

Keywords: Acetylcholinesterase; butyrylcholinesterase; organophosphate; oxime; reactivator.

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Conflict of interest statement

The authors report no conflicts of interest.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
The structures of G- and V-nerve agent series and pesticide paraoxon.
Figure 2.
Figure 2.
Structures of AChE reactivators.
Scheme 1.
Scheme 1.
Preparation of aldoxime 15. Reagents and conditions: (a) NH2OH, EtOH, 24 h, rt, 70%.
Scheme 2.
Scheme 2.
Preparation of quaternary salts 16–26. Reagents and conditions: (b) CH3I, EtOH, reflux, 24 h, 71%; (c) dibromoalkanes, DMF, 73 °C, 48 h, 33–94%.
Scheme 3.
Scheme 3.
Preparation of bisquarternary salts 30–33. Reagents and conditions: (d) DMF, 73 °C, 48 h, 53–77%; (e) bis(chloromethyl)ether, DMF, 73 °C, 48 h, 45%
Figure 3.
Figure 3.
Overlaid predicted binding modes of compounds 25 (yellow) and 26 (light pink) in hAChE (pdb id: 4ey7, left) and hBChE (pdb id: 4bds, right). The residues interacting with 25 and 26 are coloured in light green and purple, respectively.
Figure 4.
Figure 4.
Predicted binding mode of compound 30 (blue) in hAChE inhibited by sarin (A; pdb id: 5fpq), VX (B; pdb id: 6cqt) and paraoxon (C; pdb id: 5hf9).
Figure 5.
Figure 5.
Predicted binding mode of compound 17 (orange) in hBChE inhibited by VX (pdb id: 2xqf).
See this image and copyright information in PMC

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