Isatin-pyridine oxime hybrids as potential reactivators of A-242-inhibited acetylcholinesterase

Three new isatin–pyridine-2-oxime hybrids (AM01–03) were synthesized and experimentally evaluated as reactivators of acetylcholinesterase (AChE) inhibited by a surrogate of the nerve agent A-242, in comparison with their 4-oxime isomers previously reported by our research group. Furthermore, the interactions of these molecules within the AChE/A-242 complex were assessed through docking and molecular dynamics (MD) simulations. Our results show that the 2-oxime isomers, unlike their 4-oxime analogues, can reactivate AChE inhibited by the A-242 surrogate at 100 μM and are even capable of outperforming the commercial reactivator HI-6. These findings suggest that isatin–oxime hybrids may exhibit a specific biological activity—similar to that observed for obidoxime and trimedoxime—in the reactivation of AChE inhibited by A-242.