Π-stacking Interactions Research Articles

Optimizing Propylene/Propane Sieving Separation through Gate-Pressure Control within a Flexible Organic Framework.

The separation of propylene (C3H6) and propane (C3H8) is of great significance in the chemical industry, which poses a challenge due to their almost identical kinetic diameters and similar physical properties. In this work, we synthesized an ultramicroporous flexible hydrogen-bonded organic framework (named HOF-FJU-106) by using molecule 2,3,6,7-tetra(4-cyanophenyl)tetrathiafulvalene (TTF-4CN). The formation of the dimer causes the TTF-4CN molecular to bend and weaken π-stacked interactions, coupled with the flexibility of C≡N···H-C hydrogen bonds, which leads to reversible conversion between open and closed frameworks through the mutual slip of adjacent layers/columns under activation and stimulation of gas molecules. Through gas adsorption isotherms and adsorption enthalpy, HOF-FJU-106a exhibited adaptive adsorption and stronger binding affinity for C3H6, and presented a recorded gas uptake ratio of C3H6/C3H8 (23.77) among presentative HOF materials at room temperature to date. Importantly, the flexible HOF-FJU-106a shows an interesting phenomenon about the reversible gate pressure control under variable temperature, which realized the gas adsorption and separation performance enhancement for the binary C3H6/C3H8 mixtures. This strategy through designing HOFs with thermoregulatory gating effect is a powerful way to maximize the performance of materials.

Influence of Acylation by Hydroxycinnamic Acids on the Reversible and Irreversible Processes of Anthocyanins in Acidic to Basic Aqueous Solution.

In this work, the thermodynamics and kinetics of the reversible and irreversible processes of cyanidin 3,5-O-diglucoside and cyanidin 3-O-(2-O-glucosyl, 6-O-sinapoyl)glucoside-2-O-glucoside, 5-O-glucoside were studied by covering all pH range (holistic approach). The acylation (i) decreases the mole fraction of the colorless hemiketal in acidic medium and increases that of the colored quinoidal base, (ii) expands the pH domain of the flavylium cation, and (iii) moderately decreases the rate of tautomerization and isomerization of the neutral and monoanionic species. Degradation of cyanidin-3,5-O-diglucoside in a basic medium occurs in two distinct stages. After the formation of the anionic quinoidal bases (double proton loss from flavylium cation), a fast kinetic step, only observed by stopped flow, gives rise to the B4n- hydroxide adducts (n = 2,3) in equilibrium with the respective quinoidal bases An- (n = 1,2), leading to a first transient state. The quinoidal bases and B4n- adducts disappear completely from the first to a second transient state by means of two parallel reactions: (i) one reversible, giving the anionic cis- and trans-chalcones, (ii) the other irreversible, giving degradation products and exhibiting a pH-dependent bell-shaped mole fraction with maximum around pH = 12. From the second transient state, the anionic chalcones disappear completely in a few days. Acylation prevents formation of the first transient state. All of these effects are compatible with anthocyanidin-acyl π-stacking interactions (intramolecular copigmentation).

Novel versatile 5-aminoisophthalic acid modified chitosan nanofiber pads for adsorption toward Congo red, methyl orange, crystal violet, and methylene blue

To structure novel nanofiber pads for organic dye removal from dye-polluted water, we previously prepared CSP nanofiber pads by chitosan (CS) and polyethylene oxide (PEO) via electrospinning, followed by preparation of CSRP nanofiber pads through partial PEO removal from CSP, and the subsequent fabrication of CS-A nanofiber pads via grafting 5-aminoisophthalic acid (5-AIPA) to CSRP. FTIR, XRD, and elemental analyses confirmed the successful synthesis of CS-A nanofiber pads (crosslinking and crystalline degrees of 36.64 % and 4.57 %). CS-A nanofiber pads had porous nanofiber structures (diameter and pore size of 153.46 and 3.82 nm), high specific surface area (102.06 m2/g), great thermal stability (total mass loss of 50.2 %), excellent hydrophilicity (water contact angle of 12.0°), superior swelling performance (2331 %), good pH stability (pH of 3.0–11.0), and 6.8 of pHpzc, evidenced by SEM, Brunauer-Emmett-Teller (BET), thermogravimetric (TG), differential thermogravimetric (DTG), wettability, swelling, and solid addition tests. Optimum adsorption parameters (e.g., pH, dosage, and initial concentration) were selected by batches of tests on adsorption toward four organic dyes. CS-A’s surfaces were heterogeneous, and the adsorption belonged to spontaneous endothermic chemical adsorption, confirmed by kinetic and isothermal models and thermodynamic results. CS-A nanofiber pads were of great reusability and easy to be separated. Adsorption mechanisms involved electrostatic attractions, hydrogen bondings, π-stacking interactions, and pore fillings. Dynamic adsorption toward Congo red showed the Thomas model well fitted the breakthrough curves (R2 > 0.9971), showing the maximum adsorption capacity of 949.15 mg/g. Totally, CS-A nanofiber pads were effective adsorbents suitable for organic dye-containing wastewater purification.

Synthesis, crystal structure and Hirshfeld surface analysis of 2-{4-[(2-chlorophenyl)methyl]-3-methyl-6-oxopyridazin-1-yl}-N-phenylacetamide

In the title molecule, C20H18ClN3O2, the 2-chlorophenyl group is disordered to a small extent [occupancies 0.875 (2)/0.125 (2)]. The phenylacetamide moiety is nearly planar due to a weak, intramolecular C—H...O hydrogen bond. In the crystal, N—H...O hydrogen bonds and π-stacking interactions between pyridazine and phenyl rings form helical chains of molecules in the b-axis direction, which are linked by C—H...O hydrogen bonds and C—H...π(ring) interactions. A Hirshfeld surface analysis was performed, which showed that H...H, C...H/H...C and O...H/H...O interactions to dominate the intermolecular contacts in the crystal.

Effect of weak intermolecular interactions on the ionization of benzene derivatives dimers.

The interactions between π-systems in dimers of aromatic molecules lead to particularly stable conformations within the relative orientations of the monomers. Extensive research has been conducted on the properties of these complexes in the neutral state. However, in recent decades, there has been a significant surge in applications harnessing these structures for electrical purposes. Therefore, this study places particular emphasis on a deeper understanding of the redox properties of these compounds and how to modify them. To achieve this, we have focused on modeling the effect of a wide range of functional groups on the redox properties of benzene derivatives, observing a correlation between these properties and the change in the molecular dipole moment. Then, we investigated the effect of π-stacking interactions on these properties in dimers formed by either identical or different monomers. In both cases, there is an enhancement of the reducing character of the systems due to these interactions. Upon oxidation, the charge is distributed proportionally to the redox potential of each monomer. Therefore, if there is heterogeneity in these potentials, the properties of the complete cationic system will be influenced by the monomer with a greater tendency to undergo oxidation. The considered models serve as an excellent example for studying the behavior of nucleobases in DNA or aromatic amino acids, among others.

Structural and theoretical insights into the influence of thiocyanate ligands on divalent metal complexes with terpyridine derivatives

Four complexes with terpyridine derivative, thiocyanate anion, and selected d-electron metals were studied. The obtained complexes of the formulation [M(ftpy)(SCN)2(CH3OH)]•DMF (M = Mn (1), Co (2), Ni (3)) and [Cu(ftpy)(NCS)2]•H2O (4), where ftpy = 4′‐(furan-2-yl)-2,2′:6′,2′′‐terpyridine, were characterized using FTIR and UV–Vis spectroscopies, magnetic studies, elemental analysis, and single crystal X-ray crystallography. All compounds crystallize in a triclinic crystal system with space group P1¯ and 1–3 are isomorphous and isostructural. The effect of the modification of the terpyridine ligand and the presence of the thiocyanate ligand on the structure has been verified. Interesting dependence was found in the structure of compound 4, where the two thiocyanate ligands are differently coordinated, one via N and the other via S, and the formation of complex dimers connected through hydrogen bonds is observed. The π-stacking interactions and the resulting solid-state architectures of compounds 1–4 were inspected through a combination of DFT calculations, QTAIM, and NCIPlot analyses, and the stability of the complexes was studied by UV–Vis spectroscopy in various solvents.

Synergistic Effects of Unconventional Hydrogen Bonds and π-Stacking Interaction and Their Excited-State Dependence: The Origin of Unusual Photophysical Properties of Aromatic Thioketones in Acetonitrile and Hydrocarbons.

It has been established experimentally that aromatic thioketones possess several inherently unique photophysical properties, some of which are highly sensitive even to common hydrocarbon solvents. However, the deeper reasons and the underlying mechanisms remain unclear up to date. In this study, the multistate complete active space second-order perturbation theory (MS-CASPT2) has been utilized to investigate the five lowest-lying electronic states (S0, T1, S1, T2, and S2) of 4H-1-benzopyran-4-thione (BPT) in acetonitrile and hydrocarbons. The results show that the S1, T1, and T2 states of BPT are close in energy so that the T2-state-mediated S1 → T2 → T1 and T1 → T2 → S1 transitions could occur in tens of picoseconds, which exhibits little dependence on the formation of the BPT-solvent complexes and on the bulk-solvent effect. This explains why thermally activated delayed fluorescence from the S1 state has been observed for many aromatic thioketones in both inert media and hydrocarbons. Meanwhile, our calculations show that the intracomplex noncovalent interactions could be automatically adjusted by the redistribution of π-electrons in the flexible aromatic rings. This allows the S2 → S1 internal conversion to occur efficiently in the vicinity of the two-state conical intersection, which results in the remarkable changes in the S2-state lifetimes and fluorescence quantum yields of many aromatic thioketones from inert media to hydrocarbon solvents. The aforementioned inherent photophysical properties could be qualitatively understood by a simple model of frontier molecular orbitals. This model could be used to understand photophysical properties of other aromatic compounds (such as aldehydes, ketones, amines, and carboxylic acids) in different solvents.

Rotameric heterogeneity of conserved tryptophan is responsible for reduced photochemical quantum yield in cyanobacteriochrome slr1393g3.

The red/green cyanobacteriochrome (CBCR) slr1393g3 exhibits a quantum yield of only 8% for its forward photoconversion significantly lower than other species from the same CBCR subfamily. The cause for this reduced photoconversion is not yet clear, although in the related NpR6012g4 dark-state structural heterogeneity of a paramount Trp residue has been proposed to cause the formation of nonproductive subpopulation. However, there is no such information on the equivalent residue in slr1393g3, W496. Here we use solid-state NMR to explore all possible sidechain rotamers of this Trp residue and their local interactions at the atomic level. The indole nitrogen (Nε1) is used as an NMR probe, achieved by site-specific 15N-indole labeling of a quadruply Trp-deleted variant and trehalose vitrification technique. The data reveal a set of seven indole rotamers of W496 with four distinct environments for the Nε1-H group. Only a minority population of 20% is found to retain the π-stacking and hydrogen-bonding interactions with the chromophore in the dark state that has been assigned to account for complete forward photoconversion. Our results demonstrate the direct role of W496 in modulating the forward quantum yield of slr1393g3 via rearrangement of its sidechain rotameric conformations.

Human Target Proteins for Benzo(a)pyrene and Acetaminophen (And Its Metabolites): Insights from Inverse Molecular Docking and Molecular Dynamics Simulations

Acetaminophen (APAP) is a widely used analgesic and antipyretic, whereas benzo(a)pyrene (B[a]P) is a carcinogen with significant global health risks due to environmental exposure. While APAP is generally safe at therapeutic doses, co-exposure to B[a]P can exacerbate its toxicity. This study aimed to identify potential human target proteins for B[a]P and APAP through inverse molecular docking and molecular dynamics simulations. We performed inverse docking with B[a]P, APAP, and three APAP metabolites against 689 human proteins involved in various biological processes. Five proteins were selected based on high docking affinity and their involvement in multiple pathways. Molecular dynamics simulations revealed that B[a]P primarily interacted via hydrophobic and π-stacking interactions with proteins like LXR-β, HSP90α, HSP90β, and AKT1, while AM404 formed hydrogen bonds and hydrophobic interactions. The simulations confirmed that the complexes had high conformational stability, except for protein AKT1. These results provide insights into the potential impacts of B[a]P and AM404 on protein functions and their implications for understanding the toxic effects of combined exposure.

Evaluation of the electrochemical response of aromatic peptides for biodetection of dopamine

Biologically inspired aromatic peptide-based materials are gaining increasing interest as novel charge transport materials for bioelectronics due to their remarkable electrical response and inherent biocompatibility. In this work, the electrochemical response of ten aromatic amino acids and eleven aromatic peptides has been evaluated to assess the potential of incorporating peptides into electrochemical sensors not as biorecognition elements but as biocompatible electronic materials. While the electrochemical response of amino acids is null in all cases, the hexapeptide of phenylalanine (Phe) capped with eight polyethylene glycol units at the N-terminus and, especially, the cyclic dipeptide formed by two dehydro-phenylalanine residues (cyclo(ΔPhe2)), which organize in fibrillary self-assembled structures of nano- and submicrometric size, respectively, are the most electroactive peptides. Electrodes to electrochemically detect the oxidation of dopamine have been prepared using a plasma-activated polyethylene terephthalate glycol substrate covered with a poly(3,4-ethylenedioxythiophene) layer and a peptide coating deposited at the surface. The highest analytical sensitivity and the lowest limits of detection and quantifications have been obtained for the electrode coated with cyclo(ΔPhe2), which shows much better results than that without peptide. These results, on the one hand, confirm the significant role of electron transport through π-stacking interactions in the electrochemical response of peptides and, on the other hand, demonstrate that peptides can be directly used as electronic materials rather than as simple recognition elements in electrochemical biosensors.

Structural basis of nucleic acid recognition by the N-terminal cold shock domain of the plant glycine-rich protein AtGRP2

AtGRP2 is a glycine-rich, RNA-binding protein that plays pivotal roles in abiotic stress response and flowering time regulation in Arabidopsis thaliana. AtGRP2 consists of an N-terminal cold shock domain (CSD) and two C-terminal CCHC-type zinc knuckles interspersed with glycine-rich regions. Here, we investigated the structure, dynamics, and nucleic acid binding properties of AtGRP2-CSD. The 2D [1H,15N] HSQC spectrum of AtGRP2-CSD1-79 revealed the presence of a partially folded intermediate in equilibrium with the folded state. The addition of eleven residues at the C-terminus stabilized the folded conformation. The three-dimensional structure of AtGRP2-CSD1-90 unveiled a β-barrel composed of five antiparallel β-strands and a 310 helical turn, along with an ordered C-terminal extension, a conserved feature in eukaryotic CSDs. Direct contacts between the C-terminal extension and the β3-β4 loop further stabilized the CSD fold. AtGRP2-CSD1-90 exhibited nucleic acid binding via solvent-exposed residues on strands β2 and β3, as well as the β3-β4 loop, with higher affinity for DNA over RNA, particularly favoring pyrimidine-rich sequences. Furthermore, DNA binding induced rigidity in the β3-β4 loop, evidenced by 15N-{1H} NOE values. Mutation of residues W17, F26, and F37, in the central β-sheet, completely abolished DNA binding, highlighting the significance of π-stacking interactions in the binding mechanism. These results shed light on the mechanism of nucleic acid recognition employed by AtGRP2, creating a framework for the development of biotechnological strategies aimed at enhancing plant resistance to abiotic stresses.

Crystal structure and Hirshfeld surface analysis of tri-chlorido-(1,10-phenanthroline-κ2 N,N')phenyltin(IV).

The title compound, [Sn(C6H5)Cl3(C12H8N2)], which was obtained by the reaction between 1,10-phenanthroline and phenyl-tin trichloride in methanol, exhibits intra-molecular hydrogen-bonding inter-actions involving the chlorine and hydrogen atoms. Crystal cohesion is ensured by inter-molecular C-H⋯Cl hydrogen bonds, as well as Y-X⋯π and π-stacking inter-actions involving three different aromatic rings with centroid-centroid distances of 3.6605 (13), 3.9327 (14) and 3.6938 (12) Å]. Hirshfeld surface analysis and the associated two-dimensional fingerprint plots reveal significant contributions from H⋯H (30.7%), Cl⋯H/H⋯Cl (32.4%), and C⋯H/H⋯C (24.0%) contacts to the crystal packing while the C⋯C (6.2%), C⋯Cl/Cl⋯C (4.1%), and N⋯H/H⋯N (1.7%) inter-actions make smaller contributions.

Theoretical and experimental investigation on newly synthesized pyrazolopyridine derivatives: Insight into the compound activity, NLO response, and molecular dynamics

Pyrazolopyridine derivatives exhibiting biological activity are widely present in drug molecules. The title compound, ethyl 3-amino-6-methyl-4-(thiophen-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (II), was designed and synthesized and the structure characterized by spectroscopic techniques and confirmed by single-crystal X-ray diffraction. The pyrazolopyridine moiety is not quite planar and the thiophene and ester groups are rotated well out of the mean plane of the pyridine ring. N—H···N and C—H···O hydrogen bonds plus π-stacking interactions form thick layers of molecules parallel to (001). Based on structural activity relationship studies, II exhibits potent activity against fibroblast collagenase-1 complexed to a diphenyl-ether sulphone-based hydroxamic acid or Matrix Metalloproteinase (MMP-1). Theoretical simulations were performed to probe the reactivity and electronic properties of II where the quantum theory of atoms in molecules and NBO analysis was used to describe the bonding nature and charge transfer excitation. The optical and nonlinear characteristics of II are also evidenced by its hyperpolarizability response. The kinetic and thermodynamic stability of II was monitored through a computed ab-initio molecular dynamics study. In addition, a Hirshfeld surface analysis was performed to assess the intermolecular interactions. Efficient binding of II in the MMP-1 complex system has been achieved through classical molecular dynamics and molecular docking calculations. An ADMET analysis was also carried out to explore the potential future drug candidacy of II.

Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases

The HECT E3 ubiquitin ligases 1 (WWP1) and 2 (WWP2) are responsible for the ubiquitin-mediated degradation of key tumour suppressor proteins and are dysregulated in various cancers and diseases. Here we expand their limited inhibitor space by identification of NSC-217913 displaying a WWP1 IC50 of 158.3 µM (95% CI = 128.7, 195.1 µM). A structure-activity relationship by synthesis approach aided by molecular docking led to compound 11 which displayed increased potency with an IC50 of 32.7 µM (95% CI = 24.6, 44.3 µM) for WWP1 and 269.2 µM (95% CI = 209.4, 347.9 µM) for WWP2. Molecular docking yielded active site-bound poses suggesting that the heterocyclic imidazo[4,5-b]pyrazine scaffold undertakes a π-stacking interaction with the phenolic group of tyrosine, and the ethyl ester enables strong ion-dipole interactions. Given the therapeutic potential of WWP1 and WWP2, we propose that compound 11 may provide a basis for future lead compound development.

Synthesis of metal-doped covalent triazine frameworks: Incorporation into 6FDA-Durene polyimide for CO2 separation through mixed matrix membranes

The development of advanced mixed matrix membranes (MMMs) is expanding through the design of functionalized materials and efficient hybrid mass transfer mechanisms to meet the growing needs for practical and cost-effective gas separation technologies. Here, a novel series of transition metal-doped covalent triazine frameworks (M2+CTFs) was synthesized and incorporated into a 6FDA-Durene polyimide (PI) matrix in the range of 0–0.5 wt% to prepare cost-effective facilitated transport MMMs with high CO2 separation performance. Qualitative and quantitative analyses including FTIR, XPS, CHN, XRF, BET, XRD, TGA, DLS, FESEM, EDX, and TEM were carried out. The presence of nucleophilic N sites and electron-rich heterocycles in highly porous CTFs (through the π–π-stacking interactions with CO2 molecules), together with transition metal ions (Fe2+, Cu2+, and Zn2+) as the fixed site active carriers (with strong CO2 facilitated transport through the π complexation/decomplexation reaction), improves the affinity for CO2 molecules, facilitates their transport, and subsequently increases the CO2/non-polar gas selectivity of MMMs. The resultant M2+CTF/PI MMMs successfully surpass the 2008 upper bound at filler loading of 0.4 wt% for CO2/CH4 and CO2/N2 separations. Embedding M2+CTFs into the PI matrix improves the mechanical properties of the membranes. The Zn2+CTF/PI MMM represents the best separation performance with a CO2 permeability of 1408 Barrer, a CO2/N2 selectivity of 37, and a CO2/CH4 selectivity of 39, which represents a 120 %, 111 %, and 110 % increase compared to the neat PI membrane at a feed pressure of 2 bar. The excellent results of the present study indicate the high potential of cost-efficient synthesized M2+CTF particles and related facilitated transport MMMs for possible application in industrial processes.

Tracking Noncovalent Interactions of π, π-Hole, and Ion in Molecular Complexes at the Single-Molecule Level.

Noncovalent interactions involving aromatic rings, such as π-stacking and π-ion interactions, play an essential role in molecular recognition, assembly, catalysis, and electronics. However, the inherently weak and complex nature of these interactions has made it challenging to study them experimentally, especially with regard to elucidating their properties in solution. Herein, the noncovalent interactions between π and π-hole, π and cation, and π-hole and anion in molecular complexes in nonpolar solution are investigated in situ through single-molecule electrical measurements in combination with theoretical calculations. Specifically, phenyl and pentafluorobenzyl groups serve as π and π-hole sites, respectively, while Li+ and Cl- are employed as the cation and anion. Our findings reveal that, in comparison with homogeneous π···π interactions, heterogeneous π···π-hole and π···cation interactions exhibit greater binding energies, resulting in a longer binding lifetime of the molecular junctions. Meanwhile, π···Li+ and π-hole···Cl- interactions present significantly distinct binding characteristics, with the former being stronger but more flexible than the latter. Furthermore, by changing the molecular components, similar conductivity can be achieved in both molecular dimers or sandwich complexes. These results provide new insights into π- and π-hole-involved noncovalent interactions, offering novel strategies for precise manipulation of molecular assembly, recognition, and molecular device.

Self-Assembly of Thienopyrrole-Fused Thiadiazoles Containing an Amide Linker: Control of Supramolecular Polymerization Mechanism and Chiroptical Properties by Trialkoxy Side Chains.

Three thienopyrrole-fused thiadiazole (TPT) fluorescent dyes featuring a common amide linker and different alkoxy substituents on peripheral trialkoxybenzene moieties were synthesized, and their self-assembly behavior in solution was investigated. The obtained results revealed a substantial steric effect of the alkoxy substituents on the supramolecular polymerization mechanism, which results from a combination of π-stacking and hydrogen (H)-bonding interactions. Detailed spectroscopic measurements revealed that with increasing steric demand of the substituents, the supramolecular polymerization processes in pure methylcyclohexane (MCH) or a mixture of MCH and toluene become temperature-sensitive and enthalpically favorable, resulting in a change from the isodesmic assembly mechanism to the cooperative mechanism. Theoretical calculations suggested that in TPTs with bulky substituents, steric hindrance causes the H-bonding array of the amide moieties to be aligned along the stacking axis of the π-systems; thus, the H-bonding interactions are strengthened compared to those in TPTs with less bulky substituents, compensating for the weakened π-stacking interactions. A chiral TPT derivative with (S) stereogenic centers was found to form homochiral helical supramolecular assemblies that generate discernible circularly polarized luminescence. Achiral TPTs also generate helical assemblies to which preferential helicity can be imparted through the external chiral bias of the solvents (R)- and (S)-limonene.

Synthesis, mol-ecular and crystal structures of 4-amino-3,5-di-fluoro-benzo-nitrile, ethyl 4-amino-3,5-di-fluoro-benzoate, and diethyl 4,4'-(diazene-1,2-di-yl)bis-(3,5-di-fluoro-benzoate).

The crystal structures of two inter-mediates, 4-amino-3,5-di-fluoro-benzo-nitrile, C7H4F2N2 (I), and ethyl 4-amino-3,5-di-fluoro-benzoate, C9H9F2NO2 (II), along with a visible-light-responsive azo-benzene derivative, diethyl 4,4'-(diazene-1,2-di-yl)bis-(3,5-di-fluoro-benzoate), C18H14F4N2O4 (III), obtained by four-step synthetic procedure, were studied using single-crystal X-ray diffraction. The mol-ecules of I and II demonstrate the quinoid character of phenyl rings accompanied by the distortion of bond angles related to the presence of fluorine substituents in the 3 and 5 (ortho) positions. In the crystals of I and II, the mol-ecules are connected by N-H⋯N, N-H⋯F and N-H⋯O hydrogen bonds, C-H⋯F short contacts, and π-stacking inter-actions. In crystal of III, only stacking inter-actions between the mol-ecules are found.

Crystal structures of NAD(P)H nitroreductases from Klebsiella pneumoniae.

Klebsiella pneumoniae (Kp) is an infectious disease pathogen that poses a significant global health threat due to its potential to cause severe infections andits tendency to exhibit multidrug resistance. Understanding the enzymatic mechanisms of the oxygen-insensitive nitroreductases (Kp-NRs) from Kp is crucial for the development of effective nitrofuran drugs, such as nitrofurantoin, that can be activated as antibiotics. In this paper, three crystal structures of two Kp-NRs (PDB entries 7tmf/7tmg and 8dor) are presented, and an analysis of their crystal structures and their flavin mononucleotide (FMN)-binding mode is provided. The structures with PDB codes 7tmf (Kp-NR1a), 7tmg (Kp-NR1b) and 8dor (Kp-NR2) were determined at resolutions of 1.97, 1.90 and 1.35 Å, respectively. The Kp-NR1a and Kp-NR1b structures adopt an αβ fold, in which four-stranded antiparallel β-sheets are surrounded by five helices. With domain swapping, the β-sheet was expanded with a β-strand from the other molecule of the dimer. The difference between the structures lies in the loop spanning Leu173-Ala185: in Kp-NR1a the loop is disordered, whereas the loop adopts multiple conformations in Kp-NR1b. The FMN interactions within Kp-NR1/NR2 involve hydrogen-bond and π-stacking interactions. Kp-NR2 contains four-stranded antiparallel β-sheets surrounded by eight helices with two short helices and one β-sheet. Structural and sequence alignments show that Kp-NR1a/b and Kp-NR2 are homologs of the Escherichia coli oxygen-insensitive NRs YdjA and NfnB and of Enterobacter cloacae NR, respectively. By homology inference from E. coli, Kp-NR1a/b and Kp-NR2 may detoxify polynitroaromatic compounds and Kp-NR2 may activate nitrofuran drugs to cause bactericidal activity through a ping-pong bi-bi mechanism, respectively.

Energetic features of H-bonded and antiparallel π-stacked supramolecular assemblies in pyrazolones: Experimental, computational and biological analyses

The work presented herein outlines a straightforward synthetic route to produce a series of pyrazolone compounds, which are significant in both coordination chemistry and pharmaceutical research. These heterocyclic compounds were thoroughly characterized using FTIR, 1H and 13C NMR spectroscopy, and their molecular structures were conclusively determined through X-ray crystallography. The resulting supramolecular architectures feature a variety of noncovalent interactions, including conventional NH…O and CH…O hydrogen bonds, CH…halogen contacts, CH…N interactions, and offset π-π stacking. Density Functional Theory (DFT) calculations, alongside Molecular Electrostatic Potential (MEP) surface analysis and Quantum Theory of Atoms in Molecules (QTAIM)/Non-Covalent Interaction (NCI) plot methodologies, were employed to probe these interactions further. This analysis highlighted the significance of both CH…O and NH…O hydrogen bonds and revealed the critical role of antiparallel π-stacking interactions, particularly within chlorophenyl and benzonitrile substituted pyrazolones, underscoring their stabilizing effects on the molecular structure. Biological assessment against urease enzyme unveiled compound 3a as the lead inhibitor with an IC50 value of 0.71 ± 0.09 μM and 31-folds strong inhibition than thiourea, thus making pyrazolone heterocycles as potential drug candidates.