Organophosphorus compounds, including pesticides and nerve agents, irreversibly inhibit acetylcholinesterase, leading to an accumulation of acetylcholine that can cause a cholinergic crisis. Standard treatment of organophosphate poisoning relies on oxime-based reactivators, such as pralidoxime, obidoxime, or asoxime. However, these compounds have several limitations, including poor penetration through the blood-brain barrier and limited efficacy across a broad spectrum of organophosphorus compounds. For this reason, non-oxime reactivators were introduced as potential alternatives. The most promising non-oxime reactivators contain Mannich phenol moiety, imidazole group or combination of both. Some of the non-oxime derivatives demonstrated better efficacy than standard oximes during in vitro evaluation. Nevertheless, these structures have significant drawbacks such as high intrinsic acetylcholinesterase inhibition or high toxicity profile which make them unsuitable for further in vivo tests. In this review, the current progress in the development of non-oxime reactivators is summarized and their bioactivity as well as their limitations are critically discussed.

• Keywords
• Acetylcholinesterase, Butyrylcholinesterase, Nerve agent, Non-oxime, Reactivator,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• Antidotes MeSH
• Cholinesterase Inhibitors * toxicity   MeSH
• Humans MeSH
• Organophosphorus Compounds toxicity   MeSH
• Organophosphate Poisoning * drug therapy   MeSH
• Oximes MeSH
• Cholinesterase Reactivators * pharmacology   chemistry   therapeutic use   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Antidotes MeSH
• Cholinesterase Inhibitors * MeSH
• Organophosphorus Compounds MeSH
• Oximes MeSH
• Cholinesterase Reactivators * MeSH

Recent events involving nerve agents of the A-Series, a once elusive class of chemical warfare agents, have provoked a great concern in the international community. In this paper, continuing our research efforts in Medicinal Chemistry at the Brazilian Institute of Chemical, Biological, Radiological and Nuclear Defense (IDQBRN) (an OPCW-designated Laboratory for environmental samples), we explore ANMP, an A-230 surrogate, in the search for new treatment options for intoxications caused by these chemicals. Five isatin-pyridine oxime hybrids were evaluated as acetylcholinesterase (AChE) reactivators using a modified Ellman's assay. Our results indicate that monocationic hybrids with five methylene units, as well as its oxa-analog, are promising compounds for the design of new AChE reactivators.

• Keywords
• Acetylcholinesterase, Antidotes, Chemical Weapons Convention, Isatin hybrids, Nerve agents,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• Chemical Warfare Agents * toxicity   chemistry   MeSH
• Cholinesterase Inhibitors * toxicity   chemistry   MeSH
• Isatin * chemistry   pharmacology   analogs & derivatives   MeSH
• Oximes * chemistry   pharmacology   MeSH
• Computer Simulation MeSH
• Pyridines * chemistry   pharmacology   MeSH
• Cholinesterase Reactivators * pharmacology   chemistry   MeSH
• Structure-Activity Relationship MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Chemical Warfare Agents * MeSH
• Cholinesterase Inhibitors * MeSH
• Isatin * MeSH
• Oximes * MeSH
• Pyridines * MeSH
• Cholinesterase Reactivators * MeSH

Mutations on the Ras-family of small GTPases are among the most common molecular oncogenic drivers, with the HRas isoform being primarily associated with head-and-neck and genito-urinary cancers. Although once considered "undruggable," recent efforts have identified a structurally conserved surface pocket in the Ras family, designated the SI/II pocket, situated near the binding site of the guanidine exchange factor (GEF) SOS1. The SI/II pocket may represent a potential target site for a pan-Ras drug. A crystal structure representing the native state of GDP-bound HRasG12V was generated to characterize the topology of the SI/II pocket. This native-state structure was employed, together with the published structure of GppNHp-bound HRasG12V in state 1 (PDB ID: 4EFM), as a base for further molecular dynamics simulations exploring the conformational dynamics of the SI/II pocket via four generated synthetic HRas model structures. Our results show that the SI/II pocket is natively inaccessible in GDP-bound HRas yet becomes accessible in state 1 GppNHp-bound HRas systems, an effect that seems to be more evident in the mutated enzyme. This points to the GTP-bound state as a most promising target for Ras inhibitors directed at the SI/II pocket. Occlusion of the SI/II pocket is dictated by the spatial position of the α2 α helix in relation to the protein core, with α2 residue Y71 acting as a "tyrosine toggle" capable of restricting the pocket access.

• Publication type
• Journal Article MeSH

The risk of the use of toxic chemicals for unlawful acts has been a matter of concern for different governments and multilateral agencies. The Organisation for the Prohibition of Chemical Weapons (OPCW), which oversees the implementation of the Chemical Weapons Convention (CWC), considering recent events employing chemical warfare agents as means of assassination, has recently included in the CWC "Annex on Chemicals" some organophosphorus compounds that are regarded as acting in a similar fashion to the classical G- and V-series of nerve agents, inhibiting the pivotal enzyme acetylcholinesterase. Therefore, knowledge of the activity of the pyridinium oximes, the sole class of clinically available acetylcholinesterase reactivators to date, is plainly justified. In this paper, continuing our research efforts in medicinal chemistry on this class of toxic chemicals, we synthesized an A-230 nerve agent surrogate and applied a modified Ellman's assay to evaluate its ability to inhibit our enzymatic model, acetylcholinesterase from Electrophorus eel, and if the clinically available antidotes are able to rescue the enzyme activity for the purpose of relating the findings to the previously disclosed in silico data for the authentic nerve agent and other studies with similar A-series surrogates. Our experimental data indicates that pralidoxime is the most efficient compound for reactivating acetylcholinesterase inhibited by A-230 surrogate, which is the opposite of the in silico data previously disclosed.

• Keywords
• A-230, Acetylcholinesterase, Antidotes, Chemical Weapons Convention, Nerve agent surrogates,
• MeSH
• Acetylcholinesterase * metabolism   MeSH
• Antidotes pharmacology   MeSH
• Chemical Warfare Agents * toxicity   MeSH
• Cholinesterase Inhibitors * toxicity   MeSH
• Nerve Agents * toxicity   MeSH
• Organothiophosphorus Compounds toxicity   MeSH
• Oximes * pharmacology   MeSH
• Pralidoxime Compounds pharmacology   MeSH
• Pyridinium Compounds * pharmacology   MeSH
• Cholinesterase Reactivators * pharmacology   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetylcholinesterase * MeSH
• Antidotes MeSH
• Chemical Warfare Agents * MeSH
• Cholinesterase Inhibitors * MeSH
• Nerve Agents * MeSH
• Organothiophosphorus Compounds MeSH
• Oximes * MeSH
• pralidoxime MeSH Browser
• Pralidoxime Compounds MeSH
• Pyridinium Compounds * MeSH
• Cholinesterase Reactivators * MeSH