title: Synthesis and in vitro kinetic evaluation of N-thiazolylacetamido monoquaternary pyridinium oximes as reactivators of sarin, O-ethylsarin and VX inhibited human acetylcholinesterase (hAChE).
abstract: Presently available medications for treatment of organiphosphorus poisoning are not sufficiently effective due to various pharmacological and toxicological reasons. In this regard, herein we report the synthesis of a series of N-thiazolylacetamide monoquaternary pyridinium oximes and its analogs (1a-1b to 6a-6b) with diversely substituted thiazole ring and evaluation of their in vitro reactivation efficacies against nerve agent (sarin, O-ethylsarin and VX) inhibited human erythrocyte acetylcholinesterase (hAChE). Reactivation kinetics was performed to determine dissociation constant (KD), reactivity rate constant (kr) and the second order rate constant (kr2) for all the compounds and compared their efficacies with commercial antidotes viz. 2-PAM and obidoxime. All the newly synthesized oximes were evaluated for their physicochemical parameters (pKa) and correlated with their respective reactivation efficacies to assess the capability of the oxime reactivator. Three of these novel compounds showed promising reactivation efficacies toward OP inhibited hAChE. Molecular docking studies were performed in order to correlate the reactivation efficacies with their interactions in the active site of the AChE.
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: jracharya01@gmail.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: Badri Narayan
authors.initials: BN
authors.lastname: Acharya
authors.affiliation: Process Technology Development Division, Defence Research & Development Establishment, Jhansi Road, Gwalior 474 002, India.
authors.forename: G
authors.initials: G
authors.lastname: Raviraju
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 / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D002619:Chemical Warfare Agents / Q000737:chemistry* / Q000378:metabolism; D002801:Cholinesterase Reactivators / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D009946:Organothiophosphorus Compounds / Q000737:chemistry / Q000378:metabolism; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011726:Pyridinium Compounds / Q000737:chemistry; D012524:Sarin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry
chemical_list: D000110:Acetylcholinesterase; D002619:Chemical Warfare Agents; D002801:Cholinesterase Reactivators; D009946:Organothiophosphorus Compounds; D010091:Oximes; D011726:Pyridinium Compounds; D012524:Sarin; D013844:Thiazoles; C108317:ethylsarin; C009680:VX-agent
keywords: Acetylcholinesterase; Kinetics; Nerve agents; Reactivation; Thiazolylacetamides