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

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.

GRAPHICAL ABSTRACT

Keywords:

• Acetylcholinesterase
• butyrylcholinesterase
• organophosphate
• reactivator
• oxime

Acknowledgement

Authors are grateful to Bc. Magdalena Herrmannova and Karolina Pisova for their skilful technical assistance.

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

This work was supported by the Czech Science Foundation [no. 18-01734S], University of Hradec Kralove [Faculty of Science, no. SV2113-2019, VT2019-2021 and postdoctoral job positions at UHK], by Ministry of Education, Youth and Sports of the Czech Republic [project ERDF no. CZ.02.1.01/0.0/0.0/18_069/0010054], by MH CZ - DRO [University Hospital Hradec Kralove, no. 00179906] and Faculty of Military Health Sciences (Long-term development plan). Access to computing and storage facilities owned by parties and projects contributing to the National Grid Infrastructure MetaCentrum provided under the programme “Projects of Large Research, Development, and Innovations Infrastructures” (CESNET LM2015042), is greatly appreciated.