Exploring the neurotoxicity of chiral dinotefuran towards nicotinic acetylcholine receptors: Enantioselective insights into species selectivity.

Dinotefuran is a chiral neonicotinoid that is widely distributed in environmental matrices, but its health risks to different organisms are poorly understood. This study investigated the neurotoxic responses of honeybee/cotton aphid nicotinic acetylcholine receptors (nAChRs) to chiral dinotefuran at the enantiomeric scale and demonstrated the microscopic mechanism of species selectivity in nAChR-mediated enantioselective neurotoxicity. The findings indicated that (S)-dinotefuran had a higher affinity for honeybee nAChR than (R)-dinotefuran whereas both enantiomers exhibited similar bioactivity toward cotton aphid nAChR. The results of dynamic neurotoxic processes indicated the association of conformational changes induced by chiral dinotefuran with its macroscopic neurotoxicity, and (R)-dinotefuran, which exhibit low toxicity to honeybee, was found to induce significant conformational changes in the enantioselective neurotoxic reaction, as supported by the average root-mean-square fluctuation (0.35 nm). Energy decomposition results indicated that electrostatic contribution (ΔGele) is the critical energy term that leads to substantial enantioselectivity, and both Trp-51 (－2.57 kcal mol-1) and Arg-75 (－4.86 kcal mol-1), which form a hydrogen-bond network, are crucial residues in mediating the species selectivity for enantioselective neurotoxic responses. Clearly, this study provides experimental evidence for a comprehensive assessment of the health hazards of chiral dinotefuran.

Efficient degradation of imidacloprid by surface discharge cold plasma: Mechanism of interaction between ROS and molecular structure and evaluation of residual toxicity.

Incorrect use of neonicotinoid pesticides poses a serious threat to human and pollinator health, as these substances are commonly present in bee products and even drinking water. To combat this threat, the study developed a new method of degrading the pesticide imidacloprid using surface discharge cold plasma oxidation technology. The study showed that this method achieved a very high efficiency of imidacloprid degradation of 91.4%. The main reactive oxygen species (H2O2, O3, ·OH, O2-, 1O2) effectively participated in the decomposition reaction of imidacloprid. Reactive oxygen species were more sensitive to the structure of the nitroimine group. Density functional theory (DFT) further explored the sites of reactive oxygen species attack on imidacloprid and revealed the process of energy change of attacking imidacloprid. In addition, a degradation pathway for imidacloprid was proposed, mainly involving reactive oxygen species chemisorption, a ring-opening intermediate, and complete cleavage of the nitroimine group structure. Model predictions indicated that acute oral and developmental toxicity were significantly reduced after cold plasma treatment, as confirmed by insect experiments. Animal experiments have shown that plasma treatment reduces imidacloprid damage to mice hippocampal tissue structure and inhibits the reduction of brain-derived neurotrophic factor content, thus revealing the detoxification mechanism of the body.

In-silico selection of peptides for the recognition of imidacloprid.

The sensitive detection of pesticides using low-cost receptors designed from peptides can widen their uses in the environmental surveillance for emerging pollutants. In-silico selection of peptides can help accelerate the design of receptor sequence banks for a given target of interest. In this work, we started from Lymnaea stagnalis acetylcholine-binding protein Q55R mutant receptor-imidacloprid complex, available in the PDB databank, to select three primary short peptides (YSP09, DMR12, WQW13 respectively having 9, 12 and 13 amino acids (AA) in length) from the pesticide interacting zones with the A, B and C chains of the nicotinic receptor. Using molecular docking and molecular dynamics (MD) simulations, we showed that the three peptides can form complexes with the target imidacloprid, having energies close to that obtained from a reference RNR12 peptide. Combination of these peptides allowed preparing a new set of longer peptides (YSM21, PSM22, PSW31 and WQA34) that have higher stability and affinity as shown by the MM-PBSA calculations. In particular, the WQA34 peptide displayed an average binding free energy of -6.44±0.27 kcal/mol, which is three times higher than that of the reference RNR12 peptide (-2.29±0.25 kcal/mol) and formed a stable complex with imidacloprid. Furthermore, the dissociation constants (Kd), calculated from the binding free energy, showed that WQA32 (40 µM) has three orders of magnitude lower Kd than the reference RNR12 peptide (3.4 × 104 µM). Docking and RMSD scores showed that the WQA34 peptide is potentially selective to the target imidacloprid with respect to acetamiprid and clothianidin. Therefore, this peptide can be used in wet-lab experiments to prepare a biosensor to selectively detect imidacloprid.

Fluoroamide-Directed Regiodivergent C-Alkylation of Nitroalkanes.

Herein, by exploiting different activation modes of fluoroamides, we achieved α- and δ-C(sp3)-H alkylation of nitroalkanes with switchable regioselectivity. Cu catalysis enabled the interception of a distal C-centered radical by a N-centered radical to couple nitroalkanes and unactivated δ-C-H bonds. In addition, imines generated in situ by fluoroamides were trapped by nitroalkanes to realize the α-C-H alkylation of amides. Both of those scalable protocols have broad substrate scopes and good functional group tolerance.

Employing "Red Flags" to Fight the Most Neglected Diseases: Nitroaromatic as Still Suitable Tools to Treat Human and Veterinary Parasitosis.

Nitroaromatic compounds have been used for treating parasitic diseases since the 1960s. Pharmacological alternatives to treat them are under observation. However, for the most neglected diseases, such as those caused by worms and less known protozoans, nitro compounds are still among the drugs of choice, despite their well-known collateral effects. In this review, we describe the chemistry and the uses of the still most employed nitroaromatic compounds for treating parasitosis caused by worms or lesser-known protozoans. We also describe their application as veterinary drugs. The most accepted mechanism of action seems to be the same, leading to collateral effects. For this reason, a special session was dedicated to discussing toxicity, carcinogenicity, and mutagenesis, as well as the most acceptable aspects of the known structure-activity/toxicity relationships involving nitroaromatic compounds. It employed the SciFindern search tool from the American Chemical Society in the search for the most relevant bibliography within the field, exploring keyword expressions such as "NITRO COMPOUNDS" and "BIOLOGICAL ACTIVITY" (within Abstracts or Keywords) and concepts related to parasites, pharmacology and toxicology. The results were classified according to the chemical classes of nitro compounds, being the most relevant studies regarding journal impact and interest of the described results chosen to be discussed. From the found literature, it is easy to notice that nitro compounds, especially the nitroaromatic ones, are still widely used in antiparasitic therapy, despite their toxicity. They also are the best starting point in the search for new active compounds.

Treatment of the insensitive munitions compound, 3-nitro-1,2,4-triazol-5-one (NTO), in flow-through columns packed with zero-valent iron.

The need for effective technologies to remediate the insensitive munitions compound 3-nitro-1,2,4-triazol-5-one (NTO) is emerging due to the increasing use by the US Army and environmental concerns about the toxicity and aqueous mobility of NTO. Reductive treatment is essential for the complete degradation of NTO to environmentally safe products. The objective of this study is to investigate the feasibility of applying zero-valent iron (ZVI) in a continuous-flow packed bed reactor as an effective NTO remediation technology. The ZVI-packed columns treated an acidic influent (pH 3.0) or a circumneutral influent (pH 6.0) for 6 months (ca. 11,000 pore volumes, PVs). Both columns effectively reduced NTO to the amine product, 3-amino-1,2,4-triazol-5-one (ATO). The column treating the pH-3.0 influent exhibited prolonged longevity in reducing NTO, treating 11-fold more PVs than the column treating pH-6.0 influent until the breakthrough point (defined as when 85% of NTO was removed). The exhausted columns (defined as when only 10% of NTO was removed) regained the NTO reducing capacity by reactivation using 1 M HCl, fully removing NTO. After the experiment, solid-phase analysis of the packed-bed material showed that ZVI was oxidized to iron (oxyhydr)oxide minerals such as magnetite, lepidocrocite, and goethite during NTO treatment. This is the first report on the reduction of NTO and the concomitant oxidation of ZVI in continuous-flow column experiments. The evidence indicates that treatment in a ZVI-packed bed reactor is an effective approach for the removal of NTO.

Targeting Pathogenic Formate-Dependent Bacteria with a Bioinspired Metallo-Nitroreductase Complex.

Nitroreductases (NTRs) constitute an important class of oxidoreductase enzymes that have evolved to metabolize nitro-containing compounds. Their unique characteristics have spurred an array of potential uses in medicinal chemistry, chemical biology, and bioengineering toward harnessing nitro caging groups and constructing NTR variants for niche applications. Inspired by how they carry out enzymatic reduction via a cascade of hydride transfer reactions, we sought to develop a synthetic small-molecule NTR system based on transfer hydrogenation mediated by transition metal complexes harnessing native cofactors. We report the first water-stable Ru-arene complex capable of selectively and fully reducing nitroaromatics into anilines in a biocompatible buffered aqueous environment using formate as the hydride source. We further demonstrated its application to activate nitro-caged sulfanilamide prodrug in formate-abundant bacteria, specifically pathogenic methicillin-resistant Staphylococcus aureus. This proof of concept paves the way for a new targeted antibacterial chemotherapeutic approach leveraging on redox-active metal complexes for prodrug activation via bioinspired nitroreduction.

Efficient degradation of clothianidin and thiamethoxam in contaminated soil by peroxymonosulfate process.

The widespread use of neonicotinoids has led to their frequent detection in the environment and potential environmental risk in recent years. Clothianidin (CLO) and thiamethoxam (TMX), as the second generation of neonicotinoid insecticides, are usually used as seed agents with a high risk of residue in the soil. Efficient degradation of CLO and TMX in soil using peroxymonosulfate (PMS) process was investigated in the present study. The degradation efficiencies of CLO and TMX reached 91.4% and 98.6% in 60 min with the addition of 20 mM PMS at pH 5.5 and 25℃. High degradation efficiencies of CLO were achieved with a high PMS dosage and temperature or a low CLO concentration and initial pH. The degradation of CLO was reduced in the presence of high concentration of inorganic anions (Cl-, HCO3-). Soil organic matter might be one critical factor in the degradation of CLO and TMX. Radical scavenger experiments confirmed SO4•- and 1O2 were the dominant reactive species on the CLO and TMX degradation. Based on the detected degradation intermediates, the degradation pathways of CLO and TMX include dichlorination, hydroxylation, cleavage of C-N or C-C bond and further oxidation in the PMS-based soil. Overall, the PMS process is one effective and economical method for the remediation of the neonicotinoid contaminated soil.

Asymmetric C-Alkylation of Nitroalkanes via Enzymatic Photoredox Catalysis.

Tertiary nitroalkanes and the corresponding α-tertiary amines represent important motifs in bioactive molecules and natural products. The C-alkylation of secondary nitroalkanes with electrophiles is a straightforward strategy for constructing tertiary nitroalkanes; however, controlling the stereoselectivity of this type of reaction remains challenging. Here, we report a highly chemo- and stereoselective C-alkylation of nitroalkanes with alkyl halides catalyzed by an engineered flavin-dependent "ene"-reductase (ERED). Directed evolution of the old yellow enzyme from Geobacillus kaustophilus provided a triple mutant, GkOYE-G7, capable of synthesizing tertiary nitroalkanes in high yield and enantioselectivity. Mechanistic studies indicate that the excitation of an enzyme-templated charge-transfer complex formed between the substrates and cofactor is responsible for radical initiation. Moreover, a single-enzyme two-mechanism cascade reaction was developed to prepare tertiary nitroalkanes from simple nitroalkenes, highlighting the potential to use one enzyme for two mechanistically distinct reactions.

A Modern Look at Spiropyrans: From Single Molecules to Smart Materials.

Photochromic compounds of the spiropyran family have two main isomers capable of inter-switching with UV or visible light. In the current review, we discuss recent advances in the synthesis, investigation of properties, and applications of spiropyran derivatives. Spiropyrans of the indoline series are in focus as the most promising representatives of multi-sensitive spirocyclic compounds, which can be switched by a number of external stimuli, including light, temperature, pH, presence of metal ions, and mechanical stress. Particular attention is paid to the structural features of molecules, their influence on photochromic properties, and the reactions taking place during isomerization, as the understanding of the structure-property relationships will rationalize the synthesis of compounds with predetermined characteristics. The main prospects for applications of spiropyrans in such fields as smart material production, molecular electronics and nanomachinery, sensing of environmental and biological molecules, and photopharmacology are also discussed.

Multi-omics approach reveals elevated potential of bacteria for biodegradation of imidacloprid.

The residual imidacloprid, a widely used insecticide is causing serious environmental concerns. Knowledge of its biodegradation will help in assessing its residual mass in soil. In view of this, a soil microcosm-based study was performed to test the biodegradation potential of Agrobacterium sp. InxBP2. It achieved ∼88% degradation in 20 days and followed the pseudo-first-order kinetics (k = 0.0511 day-1 and t1/2=7 days). Whole genome sequencing of Agrobacterium sp. InxBP2 revealed a genome size of 5.44 Mbp with 5179 genes. Imidacloprid degrading genes at loci K7A42_07110 (ABC transporter substrate-binding protein), K7A42_07270 (amidohydrolase family protein), K7A42_07385 (ABC transporter ATP-binding protein), K7A42_16,845 (nitronate monooxygenase family protein), and K7A42_20,660 (FAD-dependent monooxygenase) having sequence and functional similarity with known counterparts were identified. Molecular docking of proteins encoded by identified genes with their respective degradation pathway intermediates exhibited significant binding energies (-6.56 to -4.14 kcal/mol). Molecular dynamic simulation discovered consistent interactions and binding depicting high stability of docked complexes. Proteome analysis revealed differential protein expression in imidacloprid treated versus untreated samples which corroborated with the in-silico findings. Further, the detection of metabolites proved the bacterial degradation of imidacloprid. Thus, results provided a mechanistic link between imidacloprid and associated degradative genes/enzymes of Agrobacterium sp. InxBP2. These findings will be of immense significance in carrying out the lifecycle analysis and formulating strategies for the bioremediation of soils contaminated with insecticides like imidacloprid.

Mechanochemistry of Spiropyran under Internal Stresses of a Glassy Polymer.

Mechanophores are powerful molecular tools used to track bond rupture and characterize mechanical damage in polymers. The majority of mechanophores are known to respond to external stresses, and we report in this study the first precedent of a mechanochemical response to internal, residual stresses that accumulate during polymer vitrification. While internal stress is intrinsic to polymers that can form solids, we demonstrate that it can dramatically affect the mechanochemistry of spiropyran probes and alter their intramolecular isomerization barriers by up to 70 kJ mol-1. This new behavior of spiropyrans (SPs) enables their application for analysis of internal stresses distribution and their mechanochemical characterization on the molecular level. Spectroscopy and imaging based on SP mechanochemistry showed high topological sensitivity and allowed us to discern different levels of internal stress impacting various locations along the polymer chain. The nature of the developed technique allows for wide-field imaging of stress heterogeneities in polymer samples of irregular shapes and dimensions, making it feasible to directly observe molecular-level manifestations of mechanical stresses that accompany the formation of a vast number of solid polymers.

Highly Diastereo- and Enantioselective Formal [4 + 2] Cyclization of Nitroalkenes and Unsaturated Ketoesters under Phase-Transfer Catalysis.

A highly diastereo- and enantioselective formal [4 + 2] cyclization of α,ß-unsaturated ketoesters with nitroalkenes through a tandem asymmetric Michael addition-intramolecular Henry reaction under dihydroquinine-based phase-transfer catalysis, leading to a one-pot construction of four contiguous stereochemical centers and multiple functional groups with excellent diastereo- and enantioselectivities in high yields, has been developed. The ee values of some products were increased to ∼100% in good yields after one crystallization.

Stimuli-Responsive Dendritic Macromolecules for Optical Detection of Metal Ions and Acidic Vapors by the Photoinduced Electron Transfer Mechanism: Paper-Based Indicator for Food Spoilage Sensing.

Visual detection of analytes has been a significant challenge in the design and development of optical chemosensors. Sensing of analytes in aqueous solution by organic molecules has encountered some issues, such as poor water solubility and quenching of optical properties. In this study, a new category of smart dendritic macromolecules was designed and synthesized by functionalization of the poly(amidoamine) (PAMAM) dendrimer with spiropyran molecules to afford a photoluminescent dendritic structure (SP-PAMAM). Smart optical sensors were prepared by physical incorporation of four different oxazolidine derivatives containing hydroxyl and nitro substituted groups into the SP-PAMAM structure. Investigation of optical properties demonstrated photoinduced electron transfer (PET) between the spiropyran end group of SP-PAMAM and oxazolidine derivatives (in a concentration of about 0.0002 M), which can result in quenching of fluorescence emission of spiropyran photoswitch in the form of merocyanine (MC). Treatment of the oxazolidine-doped SP-PAMAM samples with metal ions resulted in changes in the PET mechanism (switching on or off), as observed in the case of Fe3+, Pb2+, Cu2+, Zn2+, Cd2+, Co2+, and Ni2+ by different oxazolidine derivatives through various mechanisms (increase or decrease of fluorescence emission). These smart photoluminescent dendritic macromolecules have potential applications for photodetection of metal ions in aqueous media as optical chemosensors. In addition, the smart macromolecules displayed disconnection of PET between MC and oxazolidine and also showed red fluorescence emission under acidic conditions (pH 1-5). It is due to the protonation of the MC to MCH form and demonstrates a remarkable red shift in fluorescence spectra. The pH-responsivity of smart macromolecules was used for designing a paper-based pH indicator for visual detection of spoilage in the food industry, especially in the case of milk. The prepared papers applied on cap of the milk bottles did not show any fluorescence emission in the case of fresh milk; however, a red fluorescence emission was observed after milk spoilage as a result of adsorption of acidic volatile components generated by bacterial degradation and oxidation process on the paper surface. The reported smart papers can serve as optical portable pH indicators for timely detection of spoilage in food materials, which are usable in food packaging as smart indicator tags.

The Anisotropic Chemical Reaction Mechanism of 1,3,3-trinitroazetidine (TNAZ) under Different Shock Wave Directions by ReaxFF Reactive Molecular Dynamics Simulations.

1,3,3-Trinitroazetidine (TNAZ) has good thermal stability and low shock sensitivity, among other properties, and it has broad prospects in insensitive ammunition applications. In this study, a molecular dynamics calculation based on the ReaxFF-lg force field and multiscale shock technique (MSST) was used to simulate the shock-induced chemical reaction of TNAZ with different shock wave directions. The results showed that the shock sensitivity of TNAZ was in the order of [100] > [010] > [001]. There were significant differences in molecular arrangements in different shock directions, which affected the reaction rate and reaction path in different directions. The molecular arrangement in the [010] and [001] directions formed a "buffer" effect. The formation and cleavage of bonds, formation of small molecules and growth of clusters were analyzed to show the effect of the "buffer". The polymerization reactions in the [010] and [001] directions appeared later than that in the [100] direction, and the cluster growth in the [010] and [001] directions was slower than that in the [100] direction. In different shock loading directions, the formation and cleavage mechanisms of the N-O bonds of the TNAZ molecules were different, which resulted in differences in the initial reaction path and reaction rate in the three directions

Crystallization-Enabled Henry Reactions: Stereoconvergent Construction of Fully Substituted [N]-Asymmetric Centers.

Tetrasubstituted stereogenic carbon centers bearing a nitrogen substituent represent important motifs in medicinal chemistry and natural products; therefore, the development of efficient methods for the stereoselective synthesis of this class of compounds continues to be an important problem. This article describes stereoconvergent Henry reactions of γ,γ-disubstituted nitroalkanes to deliver highly functionalized building blocks containing up to five contiguous stereogenic centers including a fully substituted [N]-asymmetric center. Henry reactions of higher order nitroalkanes are often characterized by their reversibility and minimal accompanying thermodynamic stereocontrol. In contrast, mechanistic studies for the present case suggest a scenario in which reversibility is productively leveraged through crystallization-based stereocontrol, thereby enabling the efficient sequential π-additions of readily accessible starting materials to assemble complex acyclic stereoarrays.

Theoretical studies on 2,3,5,6-Tetra(1H-tetrazol-5-yl)pyrazine and 1,1-diamino-2,2-Dinitroethylene blending system.

To study the properties of 2,3,5,6-tetra(1H-tetrazol-5-yl)pyrazine (H4TTP) and 1,1'-diamino-2,2'-dinitroethylene (FOX-7) blending system, the structures of H4TTP, FOX-7, and H4TTP/FOX-7 dimers were optimized using density functional theory (DFT), and the mechanical properties and cohesive energy densities (CED) of H4TTP/FOX-7 blends with different mass ratios were calculated by molecular dynamics (MD) simulation. The results show that the HOMO of H4TTP is distributed on the pyrazine and tetrazole rings, while the LUMO is mainly distributed on the pyrazine ring, with a small contribution from the tetrazole ring. The HOMO of FOX-7 molecules is mainly located on the CC bonds, while the LUMO is mainly located on the nitro groups. The most stable dimer, (I), was formed when the interaction between frontier MOs is possible and hydrogen bond is formed between two monomers, which was confirmed by the Reduced Density Gradient (RDG) isosurface graph. MD studies were carried out to examine the mechanical properties and cohesive energy density of the blending systems. In monomer systems, FOX-7 has the strongest rigidity and best ductility, while H4TTP has the largest elasticity and best toughness. In the blending systems, we found that various mechanical properties and CED values were different from those of monomers, which improves the sensitivity of H4TTP and the safety of explosives.

A Mechanistic Study for Aziridination of Nitroalkenes Mediated by N-Chlorosuccinimide.

Direct aziridination of a nitrostyrene is achieved upon treatment with an alkylamine and N-chlorosuccinimide. The reaction is initiated by the Michael addition of amine to nitroalkene. Subsequent N-chlorination and nucleophilic substitution at the nitrogen atom afford 1-alkyl-2-nitroaziridine diastereoselectively. This reaction mechanism was clarified by NMR studies.

Allosteric Regulation of the Soluble Epoxide Hydrolase by Nitro Fatty Acids: a Combined Experimental and Computational Approach.

The human soluble epoxide hydrolase (hsEH) is a key regulator of epoxy fatty acid (EpFA) metabolism. Inhibition of sEH can maintain endogenous levels of beneficial EpFAs and reduce the levels of their corresponding diol products, thus ameliorating a variety of pathological conditions including cardiovascular, central nervous system and metabolic diseases. The quest for orthosteric drugs that bind directly to the catalytic crevice of hsEH has been prolonged and sustained over the past decades, but the disappointing outcome of clinical trials to date warrants alternative pharmacological approaches. Previously, we have shown that hsEH can be allosterically inhibited by the endogenous electrophilic lipid 15-deoxy-Δ12,14-Prostaglandin-J2, via covalent adduction to two cysteines, C423 and C522. In this study, we explore the properties and behaviour of three electrophilic lipids belonging to the class of the nitro fatty acids, namely 9- and 10-nitrooleate and 10-nitrolinoleate. Biochemical and biophysical investigations revealed that, in addition to C423 and C522, nitro fatty acids can covalently bind to additional nucleophilic residues in hsEH C-terminal domain (CTD), two of which predicted in this study to be latent allosteric sites. Systematic mapping of the protein mutational space and evaluation of possible propagation pathways delineated selected residues, both in the allosteric patches and in other regions of the enzyme, envisaged to play a role in allosteric signalling. The responses elicited by the ligands on the covalent adduction sites supports future fragment-based design studies of new allosteric effectors for hsEH with increased efficacy and selectivity.

Study on the mode of action between Apis mellifera (α8)2(ß1)3 nAChR and typical neonicotinoids versus flupyradifurone with different bee-toxic levels.

The health of bee populations worldwide is affected by multiple factors, of which neonicotinoids are considered to be a main reason. Although most neonicotinoids are highly toxic to bees, some of them are relatively safe. To explore the molecular mechanism of these differences in toxicity, homology modelling, molecular docking and molecular dynamics simulations were applied to study the interactions between Apis mellifera (α8)2(ß1)3 nAChR and high bee-toxic neonicotinoid (imidacloprid, IMI), medium bee-toxic (thiacloprid, THI) and low bee-toxic butenolides (flupyradifurone, FPF). It was observed that three major interactions were similar across all systems, including water-bridge networks, π-π interactions and the polar interactions between the electron-withdrawing pharmacophores and the receptor. The calculated binding free energy was similar between IMI and THI. While FPF was the lowest bee-toxic, it displayed the strongest binding free energy value, the additional C-H⋯O H-bonds with Arg80 and Trp179 were the main reason. The bee toxicities of neonicotinoids and other nAChR modulators are not only determined by receptor affinities, but also by other factors (for example physicochemical properties and metabolic detoxification). All influencing factors should be fully considered in the future design of new eco-friendly insecticides that are safe for bees.