title: Synthesis and in-vitro reactivation screening of imidazolium aldoximes as reactivators of sarin and VX-inhibited human acetylcholinesterase (hAChE).
abstract: Post-treatment of organophosphate (OP) poisoning involves the application of oxime reactivator as an antidote. Structurally different oximes are widely studied to examine their kinetic and mechanistic behavior against OP-inhibited cholinesterase enzyme. A series of structurally related 1,3-disubstituted-2-[(hydroxyiminomethyl)alkyl]imidazolium halides (5a-5e, 9a-9c) were synthesized and further evaluated for their in-vitro reactivation ability to reactivate sarin- and VX-inhibited human acetylcholinesterase (hAChE). The observed results were compared with the reactivation efficacy of standard reactivators; 2-PAM, obidoxime and HI-6. Amongst the synthesized oximes, 5a, 9a and 9b were found to be most potent reactivators against sarin-inhibited hAChE while in case of VX only 9a exhibited comparable reactivity with 2-PAM. Incorporation of pyridinium ring to the imidazole ring resulted in substantial increase in the reactivation strength of prepared reactivator. Physicochemical properties of synthesized reactivators have also been evaluated.
authors.affiliation: School of Studies in Chemistry, Pt. Ravishankar Shukla University, Raipur, C.G., 492010, India.
authors.forename: Rahul
authors.initials: R
authors.lastname: Sharma
authors.affiliation: School of Studies in Chemistry, Pt. Ravishankar Shukla University, Raipur, C.G., 492010, India.
authors.forename: Bhanushree
authors.initials: B
authors.lastname: Gupta
authors.affiliation: School of Studies in Chemistry, Pt. Ravishankar Shukla University, Raipur, C.G., 492010, India.
authors.forename: Arvind Kumar
authors.initials: AK
authors.lastname: Sahu
authors.affiliation: Process Technology Development Division, Defence Research & Development Establishment, Jhansi Road, Gwalior, M.P., 474002, India.
authors.forename: Jyotiranjan
authors.initials: J
authors.lastname: Acharya
authors.affiliation: School of Studies in Chemistry, Pt. Ravishankar Shukla University, Raipur, C.G., 492010, India.
authors.forename: Manmohan L
authors.initials: ML
authors.lastname: Satnami
authors.affiliation: School of Studies in Chemistry, Pt. Ravishankar Shukla University, Raipur, C.G., 492010, India. Electronic address: kallolkghosh@yahoo.com.
authors.forename: Kallol K
authors.initials: KK
authors.lastname: Ghosh
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D000328:Adult; D000931:Antidotes / Q000737:chemistry / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D004912:Erythrocytes / Q000201:enzymology; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D007700:Kinetics; D008297:Male; D010755:Organophosphates / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D009946:Organothiophosphorus Compounds / Q000737:chemistry / Q000378:metabolism*; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry*; D012044:Regression Analysis; D013329:Structure-Activity Relationship
chemical_list: D000110:Acetylcholinesterase; D000931:Antidotes; D002800:Cholinesterase Inhibitors; D007093:Imidazoles; D010755:Organophosphates; D009946:Organothiophosphorus Compounds; D010091:Oximes; C029899:imidazole; C009680:VX-agent
keywords: Acetylcholinesterase; Antidote; Organophosphates; Oximes; Reactivation kinetics; Reactivators