Synthesis,in vitroscreening 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.

Organophosphorus compounds and oximes: a critical review

“…In consequence a further line of research is directed to the identification of oxime structures with markedly improved reactivating potency towards OP-inhibited human BChE with the ultimate goal to provide a system where plasma and tissue BChE is transferred to a pseudo-catalytic scavenger (Radic et al 2013 ). Using different scaffolds charged and uncharged oximes were presented and showed in part a remarkable improvement in comparison to standard oximes (Sit et al 2014 ; Katalinic et al 2016 ; Zorbaz et al 2019 ; Malinak et al 2020 ). This approach is presumably of low relevance in case of poisoning by OP with short residence time such as sarin but may be beneficial in intoxications by persistent OP such as VX or lipophilic pesticides.…”

Structure and therapeutic uses of butyrylcholinesterase: Application in detoxification, Alzheimer's disease, and fat metabolism

“…The reactivation rate of 3 was determined to be 100‐ and 6‐fold higher than that of 2‐PAM and HI‐6, respectively, and 3 restored nearly 80% activity of cyclosarin‐inhibited BChE in 10 min. In the same year, Malinak et al 62 designed and synthesized a series of ChEs reactivators containing structure of isoquinoline, among which compound 4 (Figure 5) displayed stronger abilities of reactivating sarin‐, VX‐ and paraoxon‐inhibited BChE than obidoxime.…”

In silico studies, nitric oxide, and cholinesterases inhibition activities of pyrazole and pyrazoline analogs of diarylpentanoids

“…[ 37,38 ] The 4BDS protein has been even widely adopted to study the interaction of bioactive ligands and hBChE by the scientific community to date. [ 39–42 ]…”