AChE reactivator 2   

GtoPdb Ligand ID: 10074

Compound class: Synthetic organic
Comment: This compound was developed using structure-based optimization, as an antidote for acetylcholinesterase (AChE) inhibition by organophosphorus nerve agents [1]. The mechanism of enzyme reactivation depends on antidote-induced displacement of the phosphyl group from AChE's active-site serine. The main goal of the optimization campaign was to design an AChE reactivator with improved efficacy and brain penetrance compared to existing antidotes. In in vitro AChE reactivation assays, reactivator 2 outperformed the reference reactivators 2-PAM, HI-6, and obidoxime for AChE inhibited by various organophosphate nerve agents (VX, a sarin surrogate, tabun and ethyl papaoxon). Kinetic measurements and structural studies have confirmed the potential efficacy of reactivator 2 but it has not yet been evaluated in vivo.
2D Structure
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Physico-chemical Properties
Hydrogen bond acceptors 2
Hydrogen bond donors 4
Rotatable bonds 7
Topological polar surface area 91.88
Molecular weight 425.17
XLogP 5.39
No. Lipinski's rules broken 1
Canonical SMILES ON=Cc1nc(CCCCNc2c3CCCCc3[nH+]c3c2cc(Cl)cc3)ccc1O
Isomeric SMILES O/N=C\c1nc(CCCCNc2c3CCCCc3[nH+]c3c2cc(Cl)cc3)ccc1O
InChI InChI=1S/C23H25ClN4O2/c24-15-8-10-20-18(13-15)23(17-6-1-2-7-19(17)28-20)25-12-4-3-5-16-9-11-22(29)21(27-16)14-26-30/h8-11,13-14,29-30H,1-7,12H2,(H,25,28)/p+1/b26-14-
1. Santoni G, de Sousa J, de la Mora E, Dias J, Jean L, Sussman JL, Silman I, Renard PY, Brown RCD, Weik M et al.. (2018)
Structure-Based Optimization of Nonquaternary Reactivators of Acetylcholinesterase Inhibited by Organophosphorus Nerve Agents.
J. Med. Chem., 61 (17): 7630-7639. [PMID:30125110]