title: Synthesis and in vitro kinetic study of novel mono-pyridinium oximes as reactivators of organophosphorus (OP) inhibited human acetylcholinesterase (hAChE).
abstract: A series of mono pyridinium oximes linked with arenylacetamides as side chains were synthesized and their in vitro reactivation potential was evaluated against human acetylcholinesterase (hAChE) inhibited by organophosphorus inhibitors (OP) such as sarin, VX and tabun. The reactivation data of the synthesized compounds were compared with those obtained with standard reactivators such as 2-PAM and obidoxime. The dissociation constant (KD) and specific reactivity (kr) of the oximes were also determined by performing reactivation kinetics against OP inhibited hAChE. Among the synthesized compounds, oximes 1-(2-(4-cyanophenylamino)-2-oxoethyl)-4-((hydroxyimino)methyl)pyridinium chloride (12a) and 4-((hydroxyimino)methyl)-1-(2-(4-methoxyphenylamino)-2-oxoethyl)pyridinium chloride (2a) were found most potent reactivators for hAChE inhibited by sarin. In case of VX inhibited hAChE majority of the oximes have shown good reactivation efficacies. Among these oximes 1-(2-(benzylamino)-2-oxoethyl)-4-((hydroxyimino)methyl)pyridinium chloride (18a), 4-((hydroxyimino)methyl)-1-(2-(4-(methoxycarbonyl)phenylamino)-2-oxoethyl)pyridinium-chloride (14a) and 12a were found to surpass the reactivation potential of 2-PAM and obidoxime. However, the synthesized oximes showed marginal reactivation efficacies in case of tabun inhibited hAChE. The pKa value of the oximes were determined and correlated with their observed reactivation potential.
authors.affiliation: Process Technology Development Division, Defence Research & Development Establishment, Jhansi road, Gwalior 474 002, India.
authors.forename: Aditya Kapil
authors.initials: AK
authors.lastname: Valiveti
authors.affiliation: Process Technology Development Division, Defence Research & Development Establishment, Jhansi road, Gwalior 474 002, India.
authors.forename: Uma M
authors.initials: UM
authors.lastname: Bhalerao
authors.affiliation: Process Technology Development Division, Defence Research & Development Establishment, Jhansi road, Gwalior 474 002, India. Electronic address: jracharya@rediffmail.com.
authors.forename: Jyotiranjan
authors.initials: J
authors.lastname: Acharya
authors.affiliation: Process Technology Development Division, Defence Research & Development Establishment, Jhansi road, Gwalior 474 002, India.
authors.forename: Hitendra N
authors.initials: HN
authors.lastname: Karade
authors.affiliation: Process Technology Development Division, Defence Research & Development Establishment, Jhansi road, Gwalior 474 002, India.
authors.forename: Raviraju
authors.initials: R
authors.lastname: Gundapu
authors.affiliation: School of Studies in Chemistry, Jiwaji University, Gwalior, India.
authors.forename: Anand K
authors.initials: AK
authors.lastname: Halve
authors.affiliation: Process Technology Development Division, Defence Research & Development Establishment, Jhansi road, Gwalior 474 002, India.
authors.forename: Mahabir Parshad
authors.initials: MP
authors.lastname: Kaushik
mesh_terms: D000110:Acetylcholinesterase / Q000187:drug effects*; D002801:Cholinesterase Reactivators / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010091:Oximes / Q000138:chemical synthesis* / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D002801:Cholinesterase Reactivators; D009943:Organophosphorus Compounds; D010091:Oximes; D011726:Pyridinium Compounds; D000110:Acetylcholinesterase
keywords: Acetylcholinesterase; Inhibition; Nerve agents; Oxime; Reactivation; Tabun