title: Design, synthesis, and characterization of novel, nonquaternary reactivators of GF-inhibited human acetylcholinesterase.
abstract: The goal of this research was to identify structurally novel, non-quaternarypyridinium reactivators of GF (cyclosarin)-inhibited hAChE that possess the capacity to mediate in vitro reactivation of GF-inhibited human acetylcholinesterase (hAChE). New compounds were designed, synthesized and assessed in GF-inhibited hAChE assays. Structure activity relationships for AChE binding and reactivation of GF-inhibited hAChE were developed. Lead compounds from two different chemical series, represented by compounds 17 and 38, displayed proficient in vitro reactivation of GF-inhibited hAChE, while also possessing low inhibition of native enzyme.
authors.affiliation: Southwest Research Institute, Chemistry and Chemical Engineering Division, Department of Medicinal and Process Chemistry, 6220 Culebra Road, San Antonio, TX 78266, USA. Electronic address: stanton.mchardy@utsa.edu.
authors.forename: Stanton F
authors.initials: SF
authors.lastname: McHardy
authors.affiliation: Southwest Research Institute, Chemistry and Chemical Engineering Division, Department of Medicinal and Process Chemistry, 6220 Culebra Road, San Antonio, TX 78266, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Bohmann
authors.affiliation: Southwest Research Institute, Chemistry and Chemical Engineering Division, Department of Medicinal and Process Chemistry, 6220 Culebra Road, San Antonio, TX 78266, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Corbett
authors.affiliation: Southwest Research Institute, Chemistry and Chemical Engineering Division, Department of Medicinal and Process Chemistry, 6220 Culebra Road, San Antonio, TX 78266, USA.
authors.forename: Bismarck
authors.initials: B
authors.lastname: Campos
authors.affiliation: Southwest Research Institute, Chemistry and Chemical Engineering Division, Department of Medicinal and Process Chemistry, 6220 Culebra Road, San Antonio, TX 78266, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Tidwell
authors.affiliation: Southwest Research Institute, Chemistry and Chemical Engineering Division, Department of Medicinal and Process Chemistry, 6220 Culebra Road, San Antonio, TX 78266, USA.
authors.forename: Paul Marty
authors.initials: PM
authors.lastname: Thompson
authors.affiliation: Southwest Research Institute, Chemistry and Chemical Engineering Division, Department of Medicinal and Process Chemistry, 6220 Culebra Road, San Antonio, TX 78266, USA.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Bemben
authors.affiliation: Southwest Research Institute, Chemistry and Chemical Engineering Division, Department of Medicinal and Process Chemistry, 6220 Culebra Road, San Antonio, TX 78266, USA.
authors.forename: Tony A
authors.initials: TA
authors.lastname: Menchaca
authors.affiliation: Southwest Research Institute, Chemistry and Chemical Engineering Division, Department of Medicinal and Process Chemistry, 6220 Culebra Road, San Antonio, TX 78266, USA.
authors.forename: Tony E
authors.initials: TE
authors.lastname: Reeves
authors.affiliation: Southwest Research Institute, Chemistry and Chemical Engineering Division, Department of Medicinal and Process Chemistry, 6220 Culebra Road, San Antonio, TX 78266, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Cantrell
authors.affiliation: Southwest Research Institute, Chemistry and Chemical Engineering Division, Department of Medicinal and Process Chemistry, 6220 Culebra Road, San Antonio, TX 78266, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Bauta
authors.affiliation: Southwest Research Institute, Chemistry and Chemical Engineering Division, Department of Medicinal and Process Chemistry, 6220 Culebra Road, San Antonio, TX 78266, USA.
authors.forename: Ambrosio
authors.initials: A
authors.lastname: Lopez
authors.affiliation: USAMRICD Research Division, Pharmacology Branch, 3100 Ricketts Point Road, APG, MD 21010, USA.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Maxwell
authors.affiliation: USAMRICD Research Division, Pharmacology Branch, 3100 Ricketts Point Road, APG, MD 21010, USA.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Brecht
authors.affiliation: USAMRICD Research Division, Pharmacology Branch, 3100 Ricketts Point Road, APG, MD 21010, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Sweeney
authors.affiliation: USAMRICD Research Division, Pharmacology Branch, 3100 Ricketts Point Road, APG, MD 21010, USA.
authors.forename: John
authors.initials: J
authors.lastname: McDonough
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D009943:Organophosphorus Compounds; D000110:Acetylcholinesterase; C053914:cyclohexyl methylphosphonofluoridate
keywords: Acetylcholinesterase; Cyclosarin (GF); GF-inhibited hAChE; Heteroaryl keto-oximes; Reactivation; Structure–activity relationship