Design, synthesis, <i>in silico</i> studies and <i>in vitro</i> evaluation of isatin-pyridine oximes hybrids as novel acetylcholinesterase reactivators

Abstract

Organophosphorus poisoning caused by some pesticides and nerve agents is a life-threating condition that must be swiftly addressed to avoid casualties. Despite the availability of medical countermeasures, the clinically available compounds lack a broad spectrum, are not effective towards all organophosphorus toxins, and have poor pharmacokinetics properties to allow them crossing the blood-brain barrier, hampering cholinesterase reactivation at the central nervous system. In this work, we designed and synthesised novel isatin derivatives, linked to a pyridinium 4-oxime moiety by an alkyl chain with improved calculated properties, and tested their reactivation potency against paraoxon- and NEMP-inhibited acetylcholinesterase in comparison to the standard antidote pralidoxime. Our results showed that these compounds displayed comparable <i>in vitro</i> reactivation also pointed by the <i>in silico</i> studies, suggesting that they are promising compounds to tackle organophosphorus poisoning.