title: The preparation, in vitro screening and molecular docking of symmetrical bisquaternary cholinesterase inhibitors containing a but-(2E)-en-1,4-diyl connecting linkage.
abstract: Carbamate inhibitors (e.g. pyridostigmine bromide) are used as a pre-treatment for the prevention of organophosphorus poisoning. They work by blocking the native function of acetylcholinesterases (AChE) and thus protect AChE against irreversible inhibition by organophosphorus compounds. However, carbamate inhibitors are known for their many undesirable side effects related to the carbamylation of AChE. In this paper, we describe 17 novel bisquaternary compounds and have analysed their effect on AChE inhibition. The newly prepared compounds were evaluated in vitro using both human erythrocyte AChE and human plasmatic butyrylcholinesterase. Their inhibitory ability was expressed as the half maximal inhibitory concentration (IC₅₀) and then compared to the standard carbamate drugs and two AChE reactivators. One of these novel compounds showed promising AChE inhibition in vitro (nM range) and was better than the currently used standards. Additionally, a kinetic assay confirmed the non-competitive inhibition of hAChE by this novel compound. Consequently, the docking results confirmed the apparent π-π or π-cationic interactions with the key amino acid residues of hAChE and the binding of the chosen compound at the enzyme catalytic site.
authors.affiliation: Department of Toxicology, University of Defence, Faculty of Military Health Sciences, Trebesska 1575, Hradec Kralove, Czech Republic. musilek@pmfhk.cz
authors.forename: Kamil
authors.initials: K
authors.lastname: Musilek
authors.forename: Ruzena
authors.initials: R
authors.lastname: Pavlikova
authors.forename: Jan
authors.initials: J
authors.lastname: Marek
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: Martin
authors.initials: M
authors.lastname: Dolezal
authors.forename: Frank
authors.initials: F
authors.lastname: Gunn-Moore
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects*; D004912:Erythrocytes / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors