title: Novel nonquaternary reactivators showing reactivation efficiency for soman-inhibited human acetylcholinesterase.
abstract: Soman is a highly toxic nerve agent with strong inhibition of acetylcholinesterase (AChE), but of the few reactivators showing antidotal efficiency for soman-inhibited AChE presently are all permanently charged cationic oximes with poor penetration of the blood-brain barrier. To overcome this problem, uncharged reactivators have been designed and synthesized, but few of them were efficient for treating soman poisoning. Herein, we used a dual site biding strategy to develop more efficient uncharged reactivators. The ortho-hydroxylbenzaldoximes were chosen as reactivation ligands of AChE to prevent the secondary poisoning of AChE, and simple aromatic groups were used as peripheral site ligands of AChE, which were linked to the oximes in a similar way as that found in the reactivator HI-6. The in vitro experiment demonstrated that some of the resulting conjugates have robust activity against soman-inhibited AChE, and oxime 8b was highlighted as the most efficient one. Although not good as HI-6 in vitro, these new compounds hold promise for development of more efficient centrally acting reactivators for soman poisoning due to their novel nonquaternary structures, which are predicted to be able to cross the blood-brain barrier.
authors.affiliation: Laboratory of Computer-Aided Drug Design & Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Department of Military Toxicology and Biochemical Pharmacology, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing 100850, China.
authors.forename: Yan-Qin
authors.initials: YQ
authors.lastname: Liu
authors.affiliation: Department of Military Toxicology and Biochemical Pharmacology, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing 100850, China.
authors.forename: Yong-An
authors.initials: YA
authors.lastname: Wang
authors.affiliation: Department of Military Toxicology and Biochemical Pharmacology, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing 100850, China.
authors.forename: Wan-Hua
authors.initials: WH
authors.lastname: Li
authors.affiliation: Laboratory of Computer-Aided Drug Design & Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Xin-Bo
authors.initials: XB
authors.lastname: Zhou
authors.affiliation: Department of Military Toxicology and Biochemical Pharmacology, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing 100850, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Military Toxicology and Biochemical Pharmacology, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing 100850, China.
authors.forename: Chun-Qian
authors.initials: CQ
authors.lastname: Huang
authors.affiliation: Laboratory of Computer-Aided Drug Design & Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Xing-Zhou
authors.initials: XZ
authors.lastname: Li
authors.affiliation: Department of Blood Transfusion, The 307th Hospital of Chinese People's Liberation Army, Beijing 100071, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Laboratory of Computer-Aided Drug Design & Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. Electronic address: zzbcaptain@aliyun.com.
authors.forename: Zhi-Bing
authors.initials: ZB
authors.lastname: Zheng
authors.affiliation: Laboratory of Computer-Aided Drug Design & Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China; State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. Electronic address: weizhaobruce@163.com.
authors.forename: Song
authors.initials: S
authors.lastname: Li
mesh_terms: D001812:Blood-Brain Barrier; D002800:Cholinesterase Inhibitors / Q000506:poisoning*; D002801:Cholinesterase Reactivators / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D010091:Oximes / Q000493:pharmacokinetics / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000493:pharmacokinetics / Q000494:pharmacology; D012999:Soman / Q000506:poisoning*
chemical_list: D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010091:Oximes; D011726:Pyridinium Compounds; D012999:Soman; C022870:asoxime chloride
keywords: Acetylcholinesterase; Dual-site binding; Nonquaternary reactivators; Peripheral site ligand; Reactivation; Soman