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Novel Group of Ache Reactivators—Synthesis, in Vitro Reactivation and Molecular Docking Study

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Novel Group of Ache Reactivators—Synthesis, in Vitro Reactivation and Molecular Docking Study molecules Article Novel Group of AChE Reactivators—Synthesis, In Vitro Reactivation and Molecular Docking Study David Malinak 1,2, Eugenie Nepovimova 1, Daniel Jun 2,3, Kamil Musilek 1,2,* and Kamil Kuca 1,* 1 Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic; [email protected] (D.M.); [email protected] (E.N.) 2 University Hospital in Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; [email protected] 3 Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic * Correspondence: [email protected] (K.M.); [email protected] (K.K.); Tel.: +420-493-332-780 (K.K.) Received: 15 August 2018; Accepted: 5 September 2018; Published: 7 September 2018 Abstract: The acetylcholinesterase (AChE) reactivators (e.g., obidoxime, asoxime) became an essential part of organophosphorus (OP) poisoning treatment, together with atropine and diazepam. They are referred to as a causal treatment of OP poisoning, because they are able to split the OP moiety from AChE active site and thus renew its function. In this approach, fifteen novel AChE reactivators were determined. Their molecular design originated from former K-oxime compounds K048 and K074 with remaining oxime part of the molecule and modified part with heteroarenium moiety. The novel compounds were prepared, evaluated in vitro on human AChE (HssAChE) inhibited by tabun, paraoxon, methylparaoxon or DFP and compared to commercial HssAChE reactivators (pralidoxime, methoxime, trimedoxime, obidoxime, asoxime) or previously prepared compounds (K048, K074, K075, K203). Some of presented oxime reactivators showed promising ability to reactivate HssAChE comparable or higher than the used standards. The molecular modelling study was performed with one compound that presented the ability to reactivate GA-inhibited HssAChE. The SAR features concerning the heteroarenium part of the reactivator’s molecule are described. Keywords: organophosphate; acetylcholinesterase; reactivation; oxime; in vitro; molecular docking 1. Introduction Organophosphorus agents (OP) are among the most toxic compounds developed by humans. They were originally discovered as pesticides (e.g., paraoxon, methylparaoxon; Figure1), but they were further introduced as nerve agents (e.g., tabun, sarin, soman, VX; Figure1), with highly lethal effects [1]. Some OPs are also utilized as industrial agents (e.g., flame retardants). Their mechanism of action is based on the irreversible inhibition of cholinesterases [2]. The toxic effect is caused by inhibition of acetylcholinesterase (AChE), while inhibited butyrylcholinesterase (BChE) takes part as an OP bioscavenger [3]. The inhibited AChE cannot fulfil its native function of degrading the neurotransmitter acetylcholine. Thus, acetylcholine is accumulated in the synapses, causing permanent stimulation of the cholinergic (muscarinic or nicotinic) receptors. For this reason, cholinergic symptoms (e.g., miosis, salivation, lacrimation, breath depression) occur that may worsen to cholinergic crisis or death from the malfunction of breathing muscles and the depression of the breathing center in the central nervous system [4]. Molecules 2018, 23, 2291; doi:10.3390/molecules23092291 www.mdpi.com/journal/molecules Molecules 2018,, 23,, 2291x FOR PEER REVIEW 22 ofof 1617 Molecules 2018, 23, x FOR PEER REVIEW 2 of 17 Figure 1. Selected organophosphorus compounds. Figure 1. Selected organophosphorus compounds. OP intoxication is usually managed using two treatment strategies. The first pre-treatment OP intoxication is usuallyusually managedmanaged usingusing twotwo treatmenttreatment strategies.strategies. The first first pre-treatment strategy for first responders (e.g., soldiers, medical staff) consists in the protection of the organism strategy for for first first responders responders (e.g., (e.g., soldiers, soldiers, medical medical staff) staff)consists consists in the protection in the protection of the organism of the against OP attack. Pre-treatment can be performed using reversible AChE inhibitors (e.g., againstorganism OP against attack. OP Pre-treatment attack. Pre-treatment can be perfor can bemed performed using reversible using reversible AChE AChEinhibitors inhibitors (e.g., pyridostigmine chloride), stoichiometric scavengers (e.g., recombinant BChE) or catalytic (e.g.,pyridostigmine pyridostigmine chloride), chloride), stoichiometric stoichiometric scavengers scavengers (e.g., (e.g., recombinant recombinant BChE) BChE) or or catalytic bioscavengers (e.g., phosphotriesterase, paraoxonase) [5,6]. The second post-treatment strategy bioscavengers (e.g.,(e.g., phosphotriesterase, phosphotriesterase, paraoxonase) paraoxonase) [5,6 ].[5,6]. The secondThe second post-treatment post-treatment strategy strategy consists consists of managing already-OP-intoxicated organisms. The symptomatic post-treatment is focused consistsof managing of managing already-OP-intoxicated already-OP-intoxicated organisms. organisms. The symptomatic The symptomatic post-treatment post-treatment is focused is focused on the on the amelioration of the OP intoxication symptoms [2]. Atropine (parasympatholytic drug) and onamelioration the amelioration of the OP of intoxicationthe OP intoxication symptoms symp [2].toms Atropine [2]. Atropine (parasympatholytic (parasympatholytic drug) and drug) diazepam and diazepam (anticonvulsive drug), connected to supportive care, are usually used for this purpose [4]. (anticonvulsivediazepam (anticonvulsive drug), connected drug), toconnected supportive to support care, areive usually care, are used usually for this used purpose for this [4 ].purpose The causal [4]. The causal post-treatment is provided by oxime reactivators (e.g., pralidoxime, asoxime, obidoxime, post-treatmentThe causal post-treatment is provided is by provided oxime reactivators by oxime (e.g.,reactivators pralidoxime, (e.g., pralidoxim asoxime, obidoxime,e, asoxime, trimedoxime, obidoxime, trimedoxime, methoxime; 1–5; Figure 2) via nucleophilic attack of the oximate towards the trimedoxime,methoxime; 1 –5methoxime;; Figure2) via 1– nucleophilic5; Figure 2) attack via nucleophilic of the oximate attack towards of thethe OP-AChEoximate towards complex [the7]. OP-AChE complex [7]. Such drugs are able to split the OP moiety from the AChE active site and OP-AChESuch drugs complex are able [7]. to split Such the drugs OP moietyare able from to split the AChEthe OP active moiety site from and restorethe AChE its nativeactive function.site and restore its native function. The reactivation depends on many factors, e.g., OP dose, type of Therestore reactivation its native depends function. on manyThe reactivation factors, e.g., depe OP dose,nds on type many of reactivator factors, e.g., and itsOP potency dose, type against of reactivator and its potency against certain OP, delay of reactivation treatment [8]. In fact, there is not reactivatorcertain OP, and delay its ofpotency reactivation against treatment certain OP, [8]. delay In fact, of reactivation there is not atreatment single reactivator [8]. In fact, available there is not for a single reactivator available for a broad variety of OP compounds. The treatment is made even a broadsingle varietyreactivator of OP available compounds. for a Thebroad treatment variety isof made OP compounds. even more complicatedThe treatment by theis made process even of more complicated by the process of aging [9]. The OP moiety bound to the cholinesterase active site moreaging complicated [9]. The OP by moiety the process bound of to aging the cholinesterase [9]. The OP moiety active bound site is furtherto the cholinesterase coordinated viaactive loss site of is further coordinated via loss of one ester moiety (O-dealkylation). Negatively charged oxygen isone further ester moietycoordinated (O-dealkylation). via loss of Negativelyone ester moiety charged (O oxygen-dealkylation). appears, Negatively and the nucleophilic charged oxygen oxime appears, and the nucleophilic oxime reactivator is further ineffective. The aging process is well appears,reactivator and is furtherthe nucleophilic ineffective. oxime The aging reactivator process is is further well documented ineffective. for The nerve aging agents process (over is a timewell documented for nerve agents (over a time scale from minutes to hours), but some pesticides (e.g., documentedscale from minutes for nerve to hours), agents but (over some a time pesticides scale (e.g.,from methamidophos)minutes to hours), may but also some be dealkylatedpesticides (e.g., in a methamidophos) may also be dealkylated in a similar manner [10]. methamidophos)similar manner [10 may]. also be dealkylated in a similar manner [10]. Figure 2. Commercially available AChE reactivators. Figure 2. Commercially available AChE reactivators. Though the asoxime (2) waswas formerlyformerly found to bebe thethe mostmost broad-spectrumbroad-spectrum oximeoxime reactivatorreactivator Though the asoxime (2) was formerly found to be the most broad-spectrum oxime reactivator for nerve agent poisonings, it is not able to counteract, e.g., tabun or OP pesticide intoxication [11]. [11]. for nerve agent poisonings, it is not able to counteract, e.g., tabun or OP pesticide intoxication [11]. Thus, manymany scientific scientific teams teams are are trying trying to develop to develop reactivators reactivators for nerve for agent-inhibitednerve agent-inhibited
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