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New furan, thiophene, and triazole oximes were synthesized through several-step reaction paths to investigate their potential for the development of central nervous systems (CNS)-active and cholinesterase-targeted therapeutics in organophosphorus compound (OP) poisonings. Treating patients with acute OP poisoning is still a challenge despite the development of a large number of oxime compounds that should have the capacity to reactivate acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The activity of these two enzymes, crucial for neurotransmission, is blocked by OP, which has the consequence of disturbing normal cholinergic nerve signal transduction in the peripheral and CNS, leading to a cholinergic crisis. The oximes in use have one or two pyridinium rings and cross the brain-blood barrier poorly due to the quaternary nitrogen. Following our recent study on 2-thienostilbene oximes, in this paper, we described the synthesis of 63 heterostilbene derivatives, of which 26 oximes were tested as inhibitors and reactivators of AChE and BChE inhibited by OP nerve agents-sarin and cyclosarin. While the majority of oximes were potent inhibitors of both enzymes in the micromolar range, we identified several oximes as BChE or AChE selective inhibitors with the potential for drug development. Furthermore, the oximes were poor reactivators of AChE; four heterocyclic derivatives reactivated cyclosarin-inhibited BChE up to 70%, and cis,trans - 5 [2-(( Z )-2-(5-(( E )-(hydroxyimino)methyl)thiophen-2-yl)vinyl)benzonitrile] had a reactivation efficacy comparable to the standard oxime HI-6. In silico analysis and molecular docking studies, including molecular dynamics simulation, connected kinetic data to the structural features of these oximes and confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on inhibition and reactivation and their ADMET properties regarding lipophilicity, CNS activity, and hepatotoxicity, these compounds could be considered for further development of CNS-active reactivators in OP poisoning as well as cholinesterase-targeted therapeutics in neurodegenerative diseases such as Alzheimer's and Parkinson's.

The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) by organophosphates (OPs) as nerve agents and pesticides compromises normal cholinergic nerve signal transduction in the peripheral and central nervous systems (CNS) leading to cholinergic crisis. The treatment comprises an antimuscarinic drug and an oxime reactivator of the inhibited enzyme. Oximes in use have quaternary nitrogens, and therefore poorly cross the brain-blood barrier. In this work, we synthesized novel uncharged thienostilbene oximes by the Wittig reaction, converted to aldehydes by Vilsmeier formylation, and transformed to the corresponding uncharged oximes in very high yields. Eight trans,anti - and trans,syn -isomers of oximes were tested as reactivators of nerve-agent-inhibited AChE and BChE. Four derivatives reactivated cyclosarin-inhibited BChE up to 70% in two hours of reactivation, and docking studies confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on the moderate binding affinity of both AChE and BChE for all selected oximes, and in silico evaluated ADME properties regarding lipophilicity and CNS activity, these compounds present a new class of oximes with the potential for further development of CNS-active therapeutics in OP poisoning.

Toxicity of organophosphorus compounds (OPs) remains a major public health concern due to their widespread use as pesticides and the existence of nerve agents. Their common mechanism of action involves inhibition of enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) which are crucial for neurotransmission. Both chronic and acute poisoning by OPs can leave long-lasting health effects even when the patients are treated with standard medical therapy. Therefore, an increasing urgency exists to find more effective oxime reactivators for compounds which are resistant to reactivation, especially phosphoramidates. Here, we investigated in silico and in vitro interactions and kinetics of inhibition for human cholinesterases with four organophosphate pesticides-ethoprophos, fenamiphos, methamidophos and phosalone. Overall, ethoprophos and fenamiphos displayed higher potency as inhibitors for tested cholinesterases. Our results show that methamidophos-inhibited hAChE was more susceptible to reactivation than hAChE inhibited by fenamiphos by selected oximes. Molecular modelling enabled an evaluation of interactions important for specificity and selectivity of both inhibition and reactivation of cholinesterases. Two newly developed reactivators-bispyridinium triazole oxime 14A and zwitterionic oxime RS194B possess remarkable potential for further development of antidotes directed against pesticides and related phosphoramidate exposures, such as nerve agents tabun or Novichoks., (© 2021. The Author(s).)

Fatty acids (FAs) composition, 24 persistent organic pollutants (POPs), and 16 trace elements were examined in small pelagic fish (sardine, anchovy, round sardinella, chub and horse mackerels) caught by a fishing fleet for more than three years in the eastern Mediterranean Sea. Five Unmix source profiles associated with both sources, such as overlapping diet, including low-niche marine organisms and inputs from the surrounding environmental compartments were resolved. Inorganic compounds were notably more abundant in fish tissue than organochlorine xenobiotics. Comparison with the values of toxicological parameters revealed that the examined fish species are safe for human consumption, while the content of FAs emphasized the studied species as a valuable source of nutrients. A significant linear correlation was not observed between the 18 FAs and lipophilic organochlorines. Based on the obtained database, future assessments of the quality of edible fish species and the aquatic environment of the eastern Mediterranean Sea, which is known as an important fishing ground, could be significantly improved., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are primary targets in attenuating the symptoms of neurodegenerative diseases. Their inhibition results in elevated concentrations of the neurotransmitter acetylcholine which supports communication among nerve cells. It was previously shown for trans- 4/5-arylethenyloxazole compounds to have moderate AChE and BChE inhibitory properties. A preliminary docking study showed that elongating oxazole molecules and adding a new NH group could make them more prone to bind to the active site of both enzymes. Therefore, new trans- amino-4-/5-arylethenyl-oxazoles were designed and synthesised by the Buchwald-Hartwig amination of a previously synthesised trans- chloro-arylethenyloxazole derivative. Additionally, naphthoxazole benzylamine photoproducts were obtained by efficient photochemical electrocyclization reaction. Novel compounds were tested as inhibitors of both AChE and BChE. All of the compounds exhibited binding preference for BChE over AChE, especially for trans- amino-4-/5-arylethenyl-oxazole derivatives which inhibited BChE potently (IC 50 in µM range) and AChE poorly (IC 50 ≫100 µM). Therefore, due to the selectivity of all of the tested compounds for binding to BChE, these compounds could be applied for further development of cholinesterase selective inhibitors.HIGHLIGHTSSeries of oxazole benzylamines were designed and synthesisedThe tested compounds showed binding selectivity for BChENaphthoxazoles were more potent AChE inhibitors.

A library of amine, oxime, ether, epoxy and acyl derivatives of the benzobicyclo[3.2.1]octene were synthesized and evaluated as inhibitors of both human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The majority of the tested compounds exhibited higher selectivity for BChE. Structural adjustment for AChE seems to have been achieved by acylation, and the furan ring opening of furo-benzobicyclo[3.2.1]octadiene results for compound 51 with the highest AChE affinity (IC 50 = 8.3 µM). Interestingly, its analogue, an oxime ether with a benzobicyclo[3.2.1]-skeleton, compound 32 was one of the most potent BChE inhibitors in this study (IC 50 = 31 µM), but not as potent as endo- 43 , an ether derivative of the benzobicyclo[3.2.1]octene with an additional phenyl substituent (IC 50 = 17 µM). Therefore, we identified several cholinesterase inhibitors with a potential for further development as potential drugs for the treatment of neurodegenerative diseases., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

This study investigated the levels and distribution of polychlorinated biphenyls (PCBs) and organochlorine pesticides in three tissue types of farmed Bluefin tuna (Thunnus thynnus): muscle, liver and branchiae. Seven adult species were caught in 2015 at a tuna farm in the Croatian Adriatic. The organochlorine compound levels decreased in the following order: liver > muscle > branchiae while contaminant distribution in all three tissues followed the same order: ΣPCB ≫ ΣDDT > ΣHCH ~ HCB. The found POP levels indicated moderate pollution of farmed tuna and were below all limits set by current laws. Furthermore, no cytotoxic effect of the POP mixture extracted from tuna liver samples on human neuroblastoma cells was observed., (Copyright © 2020. Published by Elsevier Ltd.)

Material line defects are one-dimensional structures but the search and proof of electron behaviour consistent with the reduced dimension of such defects has been so far unsuccessful. Here we show using angle resolved photoemission spectroscopy that twin-grain boundaries in the layered semiconductor MoSe 2 exhibit parabolic metallic bands. The one-dimensional nature is evident from a charge density wave transition, whose periodicity is given by k F /π, consistent with scanning tunnelling microscopy and angle resolved photoemission measurements. Most importantly, we provide evidence for spin- and charge-separation, the hallmark of one-dimensional quantum liquids. Our studies show that the spectral line splits into distinctive spinon and holon excitations whose dispersions exactly follow the energy-momentum dependence calculated by a Hubbard model with suitable finite-range interactions. Our results also imply that quantum wires and junctions can be isolated in line defects of other transition metal dichalcogenides, which may enable quantum transport measurements and devices., Competing Interests: The authors declare no competing financial interests.

We study Majorana zero energy modes (MZEM) that occur in an s-wave superconducting surface, at the ends of a ferromagnetic (FM) chain of adatoms, in the presence of Rashba spin-orbit interaction (SOI) considering both non self-consistent and self-consistent superconducting order. We find that in the self-consistent solution, the average superconducting gap function over the adatom sites has a discontinuous drop with increasing exchange interaction at the same critical value where the topological phase transition occurs. We also study the MZEM for both treatments of superconducting order and find that the decay length is a linear function of the exchange coupling strength, chemical potential and superconducting order. For wider FM chains the MZEM occur at smaller exchange couplings and the slope of the decay length as a function of exchange coupling grows with chain width. Thus we suggest experimental detection of different delocalization of MZEM in chains of varying widths. We discuss similarities and differences between the MZEM for the two treatments of the superconducting order.