title: Preparation, in vitro screening and molecular modelling of symmetrical 4-tert-butylpyridinium cholinesterase inhibitors--analogues of SAD-128.
abstract: Carbamate inhibitors (e.g., pyridostimine bromide) are used as a pre-exposure treatment for the prevention of organophosphorus poisoning. They work by blocking acetylcholinesterase's (AChE) native function and thus protect AChE against irreversible inhibition by organophosphorus compounds. However, carbamate inhibitors are known for many undesirable side-effects related to the carbamylation of AChE. In this Letter, 19 analogues of SAD-128 were prepared and evaluated as cholinesterase inhibitors. The screening results showed promising inhibitory ability of four compounds better to used standards (pralidoxime, obidoxime, BW284c51, ethopropazine, SAD-128). Four most promising compounds were selected for further molecular docking studies. The SAR was stated from obtained data. The former receptor studies were reported and discussed. The further in vivo studies were recommended in the view of OP pre-exposure treatment.
authors.affiliation: University of Defence, Faculty of Military Health Sciences, Department of Toxicology, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
authors.forename: Kamil
authors.initials: K
authors.lastname: Musilek
authors.forename: Jan
authors.initials: J
authors.lastname: Roder
authors.forename: Marketa
authors.initials: M
authors.lastname: Komloova
authors.forename: Ondrej
authors.initials: O
authors.lastname: Holas
authors.forename: Martina
authors.initials: M
authors.lastname: Hrabinova
authors.forename: Miroslav
authors.initials: M
authors.lastname: Pohanka
authors.forename: Vlastimil
authors.initials: V
authors.lastname: Dohnal
authors.forename: Veronika
authors.initials: V
authors.lastname: Opletalova
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
authors.forename: Young-Sik
authors.initials: YS
authors.lastname: Jung
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D008958:Models, Molecular; D010755:Organophosphates / Q000737:chemistry; D011726:Pyridinium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D010755:Organophosphates; D011726:Pyridinium Compounds; C016845:SAD-128; D000110:Acetylcholinesterase