Noncovalent interactions are central to catalysis, promoting ground-state bond activation and transition-state stabilization. Arsenite biomethylation by AsIII S-adenosylmethionine methyltransferase (ArsM) is critical for detoxification, yet its variable efficiency remains mechanistically elusive. Here, we uncover the pivotal role of noncovalent interactions in modulating the methylation efficiency. Guided by MD simulations of SAM- and As-bound ArsM, which reveal stabilizing interactions from conserved Gly91 and Tyr70, we designed thioimidazolium-based methylating agents (1-7) to emulate the enzymatic process and incorporate tailored intramolecular interactions to modulate S-CH3 bond activation. Notably, bis- (4) and tetra-thioimidazolium (7) derivatives exhibit dramatic enhancements in methylation rate─up to 80-fold─and remarkably high efficiencies compared to agent 1 (98% for 7 vs 16% for 1), driven by cooperative and synchronized noncovalent interactions within conformationally locked frameworks that are entirely absent in 1. In agent 7, a closed-loop arrangement of four sulfur centers enables electron delocalization across S-CH3 units, substantially lowering the methyl transfer activation barrier. Furthermore, the in situ generation of thione byproducts facilitates the reduction of pentavalent arsenic intermediates, completing the biomimetic methylation cycle. These findings establish a direct structure-function correlation between noncovalent interaction networks and methylation efficiency, offering a new strategy for designing efficient synthetic methylating agents.

Organomercurials (RHg+), especially methylmercury (MeHg+) and ethylmercury (EtHg+), are considered to be more neurotoxic than the inorganic counterpart (Hg2+). They cause massive DNA damage in cells, especially in neurons, where cellular glutathione (GSH) levels are significantly low. However, the mechanism by which RHg+ exerts massive DNA damage at cytotoxic concentrations in brain cells remains obscure. In this study, we investigated the effect of RHg+ on the structural and electronic properties of nucleosides and its effects on DNA damage. The direct interaction of RHg+ with the nucleoside significantly weakens N-glycosidic bonds, decreases the C-H bond energy of sugar moieties, and increases the electrophilicity of the C8-center of purine bases. As a consequence, RHg+-conjugated DNA molecules are extremely labile and highly sensitive to any nucleophiles/radicals present in GSH-depleted cells and, thus, undergo enhanced oxidative and unusual alkylative DNA damage. We also report a functional model of organomercurial lyase, which showed excellent cytoprotective effect against RHg+-induced cytotoxicity; this reverses the activity of glutathione reductase inhibited by MeHgCl and ceases oxidative and alkylating DNA damage. This intriguing finding provides new mechanistic insight into the mode of action of organomercurials in GSH-depleted cells and their adverse effects on individuals with neurodegenerative disorders associated with oxidative stress.

The newly synthesized benzimidazole-based [E2]-donor ligands (E = S or Se) (L1 -L4) on reaction with copper(II) chloride and copper(II) acetate involved reduction of Cu(II) to Cu(I) and yielded copper(I) complexes. The ligands L1 -L3 formed stable 20-membered metallocyclic binuclear Cu(I)-complexes of stoichiometry, [Cu2Cl2(L1-L3)2] (5-7) and [Cu2(OAc)2(L1-L3)2] (9-11). Interestingly, L4 ligand yielded a stable complex, [Cu2Cl2(L4)2] (8) with a chloride anion, but with acetate it formed an unstable complex, [Cu2(OAc)2(L4)2] (12). ESI-mass of coordination compounds 5-12, supported the characteristic molecular ion peaks/ fragmented peaks for their ions. NMR study of ligands and complexes, single crystal x-ray crystallography of ligands L1, L2, L4 and complex 6, as well as DFT studies of all ligands and complexes are reported for characterization of ligands and complexes (1-12). Compound 12 with -NCH2CH2OH moiety in the ligand L4 showed very unusual behavior as compared to the compound 11 with -NCH3 moiety in the ligand L3. It degraded under mild conditions to form copper selenide (Cu2-xSe) nanoparticles in the solution, which were characterized using various techniques, such as TEM, SEM and EDX. The plausible mechanism for the instability of the complex 12 even at low temperature (at 0 degrees C), leading to the formation of Cu2-xSe nanoparticles, has been discussed in this paper.

This study investigated the potential of plywood reinforced with short hemp fibers and bonded with lignin-phenol-formaldehyde adhesives for structural applications. Furthermore, bond quality was examined by the evaluation of the physical and mechanical properties of the fabricated plywood as per standard methods of tests. The plywood bonded with phenol-formaldehyde resin was used as a control group. Four different types of plywoods were produced by the hot-pressing method. Subsequently, moisture content, density, modulus of elasticity, modulus of rupture, tensile strength, and matrix shear strength were tested and results were evaluated. Field emission scanning electron microscopy was used to analyze the fractured surface of tested plywood. The results indicated that lignin-phenol-formaldehyde resin with a replacement of phenol up to 50% weight with lignin (sodium lignosulfonate) can be utilized for bonding plywood. The modulus of elasticity of plywood bonded with lignin-phenol-formaldehyde resin at 7.65 GPa is higher than the phenol-formaldehyde resin at 5.28 GPa. The other properties of both lignin-phenol-formaldehyde and phenol-formaldehyde bonded plywood were found to be similar. In addition, the 3-point bending strength of plywood reinforced with short hemp fibers increased the strength of the composite by 95.3 MPa compared with the control group of 78.5 MPa. Furthermore, the moisture content, modulus of rupture, tensile strength, and shear strength test results of fiber-reinforced plywood confirm the specific requirements of structural plywood.

Hydrogen peroxide plays a crucial role in the melanogenesis process by regulating the activity of the key melanin-forming enzyme tyrosinase, responsible for the browning of fruits, vegetables, and seafood. Therefore, a molecule with dual activities, both efficient tyrosinase inhibition and strong hydrogen peroxide degrading ability, may act as a promising antibrowning agent. Herein, we report highly efficient selone-based mushroom tyrosinase inhibitors 2 and 3 with remarkable glutathione peroxidase (GPx) enzyme-like activity. The presence of benzimidazole moiety enhances the tyrosinase inhibition efficiency of selone 2 (IC50 = 0.4 μM) by almost 600 times higher than imidazole-based selone 1 (IC50 = 238 μM). Interestingly, the addition of another aromatic ring to the benzimidazole moiety has led to the development of an efficient lipid-soluble tyrosinase inhibitor 3 (IC50 = 2.4 μM). The selenium center and the -NH group of 2 and 3 are extremely crucial to exhibit high GPx-like activity and tyrosinase inhibition potency. The hydrophobic moiety of the inhibitors (2 and 3) further assists them in tightly binding at the active site of the enzyme and facilitates the C═Se group to strongly coordinate with the copper ions. Inhibitor 2 exhibited excellent antibrowning and polyphenol oxidase inhibition properties in banana and apple juice extracts.

The synthesis, characterization, and X-ray structure of a series of mono, tri, and polynuclear copper complexes of benzimidazole-based N-substituted thiones, Bz(Me)S(H) (10) and Bz(OH)S(H) (11), and N,N'-disubstituted, Bz(Me)S(Me) (12) and Bz(OH)S(Me) (13) are reported here. The X-ray structure analyses of the copper-thione complexes have revealed that the coordination behaviour and the geometry of the central metal ion in these complexes are significantly dependent on the type of the counter anion used in the reaction. For instance, the reactions of benzimidazolebased thiones with CuCl2 afforded mononuclear trigonal planar Cu(I) complexes 14, 15, 18, and 19. On contrast, upon reaction with CuSO4, 10 afforded the trinuclear copper complex 16, in which thione 10 acts as a bridging as well as terminal ligand, leading to the formation of a six-membered Cu3S3 cluster. The chair-form of six-membered Cu3S3 ring is further stabilized by six intramolecular H-bonding interactions, with overall stabilization energy of 19.28 kcal.mol(-1), between the free NH group of 10 and O atom of the counter anion SO42-. Whereas, when thione 10 was reacted with CuI, a 1D-polymeric chain-like copper complex 17 was obtained as a thermodynamically stable product, in which both 10 and iodine act as bridging ligand. The 3D network of complexes has revealed that these copper-thione compounds are stabilized by the presence of various types of intermolecular and intramolecular H-bonding and pi pi stacking interactions in the solid state. NBO analysis of the crystal geometries revealed that the strength of these interactions ranging from 0.14 to 5.67 kcal.mol(-1). We have also demonstrated that the N-substituted thiones have excellent reactive oxygen species (ROS) scavenging property and, thus, protect biomolecules including DNA and protein against Cu(I)-mediated oxidative damage.

The Hg-C bond of MeHgCl, a ubiquitous environmental toxicant, is notoriously inert and exceedingly difficult to cleave. The cleavage of the Hg-C bond of MeHgCl at low temperature, therefore, is of significant importance for human health. Among various bis(imidazole)-2-selones LnSe (n=1-4, or 6), the three-spacer L3Se shows extraordinarily high reactivity in the degradation of various mercury alkyls including MeHgCl because of its unique ability to coordinate through kappa(2)-fashion, in which both the Se atoms simultaneously attack the Hg center of mercury alkyls for facile Hg-C bond cleavage. It has the highest softness (sigma) parameter and the lowest HOMO(LnSe)-LUMO(MeHgX) energy gap and, thus, L3Se is the most reactive among LnSe towards MeHgX (X=Cl or I). L3Se is highly efficient, more than L1Se, in restoring the activity of antioxidant enzyme glutathione reductase (GR) that is completely inhibited by MeHgCl; 80 % GR activity is recovered by L3Se relative to 50 % by L1Se. It shows an excellent cytoprotective effect in liver cells against MeHgCl-induced oxidative stress by protecting vital antioxidant enzymes from inhibition caused by MeHgCl and, thus, does not allow to increase the intracellular reactive oxygen species (ROS) levels. Furthermore, it protects the mitochondrial membrane potential (Delta psi(m)) from perturbation by MeHgCl. Major Hg-responsive genes analyses demonstrate that L3Se plays a significant role in MeHg+ detoxification in liver cells.

In the present study, an ionic liquid (IL), known as green solvent, 1-butyl-3-methylimidazolium tetrafluoroborate (BMIM-BF4) with four carbons in the hydrophobic chain (C-4) has been used as an additive to modify the self-assembled aggregates of an anionic surfactant sodium dodecyl sulfate (SDS) and then the evolution of the liquid crystalline phases has been investigated. Small angle synchrotron x-ray diffraction study has revealed an unprecedented phase sequence where a hexagonal phase (H-I) of direct cylindrical micelles is observed to evolve to another hexagonal phase (H-II) of, again, direct cylindrical micelles with a lamellar phase () as the intermediate. The rheological data and the theoretical calculations have confirmed the phases. To understand such a phase behaviour of the system, the work is extended by considering the ionic liquids with the same head group but of shorter (C-2) and longer (C-10) hydrocarbon chains compared to BMIM-BF4. While the shorter chain IL causes the hexagonal phase to form rectangular (R) phase, the longer chain is observed to induce the lamellar phase (). The molecular mechanism of appearance of such different phases has been discussed. [GRAPHICS] .

The sulfur-containing antioxidant molecule ergothioneine with an ability to protect metalloenzymes from reactive oxygen species (ROS) has attracted significant interest in both chemistry and biology. Herein, we demonstrated the importance of hydrogen bonding in S-oxygenation reactions between various thiones and H2O2 and its significance in protecting the metal ion from H2O2-mediated oxidation. Among all imidazole- and benzimidazole-based thiones (1-10), ImMeSH (2) showed the highest reactivity toward H2O2-almost 10 and 75 times more reactive than N, N'-disubstituted ImMeSMe (5) and BzMeSMe (10), respectively. Moreover, metal-bound ImMeSH (2) of [TpmCu(2)]+ (13) was found to be 51 and 1571 times more reactive toward H2O2 than the metal-bound ImMeSMe (5) of [TpmCu(5)]+ (16), and BzMeSMe (10) of [TpmCu(10)]+ (21), respectively. The electron-donating N-Me substituent and the free N-H group at the imidazole ring played a very crucial role in the high reactivity of ImMeSH toward H2O2. The initial adduct formation between ImMeSH and H2O2 (ImMeSH·H2O2) was highly facilitated (-23.28 kcal mol-1) due to the presence of a free N-H group, which leads to its faster oxygenation than N, N'-disubstituted ImMeSMe (5) or BzMeSMe (10). As a result, ImMeSH (2) showed a promising effect in protecting the metal ion from H2O2-mediated oxidation. It protected biomolecules from Cu(I)-mediated oxidative damage of through coordination to the Cu(I) center of [TpmCu(CH3CN)]+ (11), whereas metal-bound ImMeSMe or BzMeSMe failed to protect biomolecules under identical reaction conditions.

Methylation and demethylation of mercury compounds are two important competing processes that control the net production of highly toxic mercury alkyls, methylmercury (MeHg+) and dimethylmercury (Me2Hg), in environment. Although the microbial and the photochemical methylation and demethylation processes are well studied in recent years but the chemical methylation and demethylation processes have not been studied well. Herein, we report for the first time that the CuSe nanosheet has remarkable ability to activate the highly inert Hg-C bonds of various MeHg+ and Me2Hg compounds at room temperature (21 degrees C). It facilitates the conversion of MeHg+ into Me2Hg in the absence of any proton donors. Whereas, in the presence of any proton source, it has unique ability to degrade MeHg+ into CH4 and inorganic mercury (Hg2+). Detailed studies revealed that the relatively fast Hg-C bond cleavage was observed in case of MeHgSPh or MeHgI in comparison to MeHgCl, indicating that the Hg-C bond in MeHgCl is relatively inert in nature. On the other hand, the Hg-C bond in Me2Hg is considered to be exceedingly inert and, thus, difficult to cleave at room temperature. However, CuSe nanosheets showed unique ability to degrade Me2Hg into CH4 and Hg2+, via the formation of MeHg+, under acidic conditions at room temperature. DFT calculations revealed that the Hg-C bond activation occurs through adsorption on the surface of (100)-faceted CuSe nanosheets.

Synthetic organic molecules, which can selectively convert excess intracellular copper (Cu) ions to nanozymes with an ability to protect cells from oxidative stress, are highly significant in developing therapeutic agents against Cu-related disorder like Wilson's disease. Here, we report 1,3-bis(2-hydroxyethyl)-1 H-benzoimidazole-2-selenone (1), which shows a remarkable ability to remove Cu ion from glutathione, a major cytosolic Cu-binding ligand, and thereafter converts it into copper selenide (CuSe) nanozyme that exhibits remarkable glutathione peroxidase-like activity, at cellular level of H2O2 concentration, with excellent cytoprotective effect against oxidative stress in hepatocyte. Cu-driven deselenization of 1, under physiologically relevant conditions, occurred in two steps. The activation of C═Se bond by metal ion is the crucial first step, followed by cleavage of the metal-activated C═Se bond, initiated by the OH group of N-(CH2)2OH substituent through neighboring group participation (deselenization step), resulted in the controlled synthesis of various types of Cu2-xSe nanocrystals (NCs) (nanodisks, nanocubes, and nanosheets) and tetragonal Cu3Se2 NCs, depending upon the oxidation state of the Cu ion used to activate the C═Se bond. Deselenization of 1 is highly metal-selective. Except Cu, other essential metal ions, including Mn2+, Fe2+, Co2+, Ni2+, or Zn2+, failed to produce metal selenide under identical reaction conditions. Moreover, no significant change in the expression level of Cu-metabolism-related genes, including metallothioneines MT1A, is observed in liver cells co-treated with Cu and 1, as opposed to the large increase in the concentrations of these genes observed in cells treated with Cu alone, suggesting the participation of 1 in Cu homeostasis in hepatocyte.

Here we report the coordination behaviour of an imidazole-based [S-1]-donor ligand, 1,3-dimethylimidazole-2(3H)-thione (L1), and [S-2]-donor ligand, 3,30-methylenebis(1-methyl-imidazole-2(3H)-thione) (L2) or 4,4'-(3,3'-methylenebis-(2-thioxo-2,3-dihydro-imidazole-3,1-diyl))dibutanoic acid (L3), with HgX2 (X = Cl, Br or I) in solution and the solid state. NMR, UV-Vis spectroscopic, and single crystal X-ray studies demonstrated that L1 or L2 coordinated rapidly and reversibly to the mercury center of HgX2 through the thione moiety. Treatment of L2 with HgCl2 or HgBr2 afforded 16-membered metallacycle k(1)-(L2)(2)Hg2Cl4 or k(1)-(L2)(2)Hg2Br4 where two Cl or Br atoms are located inside the ring. In contrast, treatment of L2 with Hgl(2) afforded a chain-like structure of k(1)-[L2Hgl(2)](n), possibly due to the large size of the iodine atom. Interestingly, [S-1] and [S-2]-donor ligands (L1, L2, and L3) showed an excellent efficacy to protect liver cells against HgCl2 induced toxicity and the strength of their efficacy is in the order of L3 > L2 > L1. 30% decrease of ROS production was observed when liver cells were co-treated with HgCl2 and L1 in comparison to those cells treated with HgCl2 only. In contrast, 45% and 60% decrease of ROS production was observed in the case of cells co-treated with HgCl2 and thiones L2 and L3, respectively, indicating that [S-2]-donor ligands L2 and L3 have better cytoprotective effects against oxidative stress induced by HgCl2 than [S-1]-donor ligand L1. Water-soluble ligand L3 with N-(CH2)(3)CO2H substituents showed a better cytoprotective effect against HgCl2 toxicity than L2 in liver cells.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

The direct C2-H oxidation and imination of a wide variety of azoles was achieved by using a commercially available simple K2CO3/I2 reagent combination. The iodinated azole adduct, produced via the in situ generation of N-heterocyclic carbene, is the key intermediate for C2-H oxidation, imination, and amination of azoles. Significantly, these reactions proceed under mild conditions with high to excellent yields, are scalable to large quantity and exhibit a broad substrate scope. Interestingly, this direct C2-H imination method allowed us to access various pharmacologically active N6-alkyl or N6-aryl substituted benzimidazoquinazolinone scaffolds through intramolecular C-H imination in a sequential one-pot reaction.