Design, synthesis and evaluation of new classes of nonquaternary reactivators for acetylcholinesterase inhibited by organophosphates. 2018

Zhao Wei, and Huanglei Bi, and Yan-Qin Liu, and Hui-Fang Nie, and Lin Yao, and Sheng-Zheng Wang, and Jun Yang, and Yong-An Wang, and Xueying Liu, and Zhi-Bing Zheng
Department of Medicinal Chemistry, School of Pharmacy, Fourth Military Medical University, Xi'an 300071, China. Electronic address: weizhaobruce@163.com.

A new series of nonquaternary conjugates for reactivation of both nerve agents and pesticides inhibited hAChE were described in this paper. It was found that substituted salicylaldehydes conjugated to aminobenzamide through piperidine would produce efficient reactivators for sarin, VX and tabun inhibited hAChE, such as L6M1R3, L6M1R5 to L6M1R7, L4M1R3 and L4M1R5 to L4M1R7. The in vitro reactivation experiment for pesticides inhibited hAChE of these new synthesized oximes were conducted for the first time. Despite they were less efficient than obidoxime, some of them were highlighted as equal or more efficient reactivators in comparison to 2-PAM. It was found that introduction of peripheral site ligands could increase oximes' binding affinity for inhibited hAChE in most cases, which resulted in greater reactivation ability.

UI MeSH Term Description Entries
D010575 Pesticides Chemicals used to destroy pests of any sort. The concept includes fungicides (FUNGICIDES, INDUSTRIAL); INSECTICIDES; RODENTICIDES; etc. Pesticide
D002800 Cholinesterase Inhibitors Drugs that inhibit cholinesterases. The neurotransmitter ACETYLCHOLINE is rapidly hydrolyzed, and thereby inactivated, by cholinesterases. When cholinesterases are inhibited, the action of endogenously released acetylcholine at cholinergic synapses is potentiated. Cholinesterase inhibitors are widely used clinically for their potentiation of cholinergic inputs to the gastrointestinal tract and urinary bladder, the eye, and skeletal muscles; they are also used for their effects on the heart and the central nervous system. Acetylcholinesterase Inhibitor,Acetylcholinesterase Inhibitors,Anti-Cholinesterase,Anticholinesterase,Anticholinesterase Agent,Anticholinesterase Agents,Anticholinesterase Drug,Cholinesterase Inhibitor,Anti-Cholinesterases,Anticholinesterase Drugs,Anticholinesterases,Cholinesterase Inhibitors, Irreversible,Cholinesterase Inhibitors, Reversible,Agent, Anticholinesterase,Agents, Anticholinesterase,Anti Cholinesterase,Anti Cholinesterases,Drug, Anticholinesterase,Drugs, Anticholinesterase,Inhibitor, Acetylcholinesterase,Inhibitor, Cholinesterase,Inhibitors, Acetylcholinesterase,Inhibitors, Cholinesterase,Inhibitors, Irreversible Cholinesterase,Inhibitors, Reversible Cholinesterase,Irreversible Cholinesterase Inhibitors,Reversible Cholinesterase Inhibitors
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000067397 Nerve Agents A class of compounds that adversely affect the transmission of impulses through the NERVOUS SYSTEM. Nerve Agent,Nerve Gas,Agent, Nerve,Agents, Nerve,Gas, Nerve
D000110 Acetylcholinesterase An enzyme that catalyzes the hydrolysis of ACETYLCHOLINE to CHOLINE and acetate. In the CNS, this enzyme plays a role in the function of peripheral neuromuscular junctions. EC 3.1.1.7. Acetylcholine Hydrolase,Acetylthiocholinesterase,Hydrolase, Acetylcholine
D012524 Sarin An organophosphorus ester compound that produces potent and irreversible inhibition of cholinesterase. It is toxic to the nervous system and is a chemical warfare agent. Sarin Gas,o-Isopropylmethyl Phosphonofluoridate,ortho-Isopropylmethyl Phosphonofluoridate,Gas, Sarin,Phosphonofluoridate, o-Isopropylmethyl,Phosphonofluoridate, ortho-Isopropylmethyl,o Isopropylmethyl Phosphonofluoridate,ortho Isopropylmethyl Phosphonofluoridate
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs
D062105 Molecular Docking Simulation A computer simulation technique that is used to model the interaction between two molecules. Typically the docking simulation measures the interactions of a small molecule or ligand with a part of a larger molecule such as a protein. Molecular Docking,Molecular Docking Simulations,Molecular Docking Analysis,Analysis, Molecular Docking,Docking Analysis, Molecular,Docking Simulation, Molecular,Docking, Molecular,Molecular Docking Analyses,Molecular Dockings,Simulation, Molecular Docking
D020536 Enzyme Activators Compounds or factors that act on a specific enzyme to increase its activity. Activators of Enzymes,Activators, Enzyme,Enzymes Activators

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