Charge-assisted Hydrogen Bonds Research Articles

A novel crystalline molecular salt of sulfamethoxazole and amantadine hybridizing antiviral-antibacterial dual drugs with optimal in vitro/vivo pharmaceutical properties

In order to exploit the advantages to the full of multidrug salification strategy in amending the pharmaceutical properties of drugs both in vitro and in vivo, and further to open up a new way for its applications in bacteria-virus mixed cross-infection drugs, a novel dual-drug crystalline molecular salt hybridizing antibacterial drug sulfamethoxazole (SFM) with antiviral ingredient amantadine (ATE), namely SFM-ATE, is successfully designed and synthesized via multidrug salification strategy oriented by proton exchange reaction. The crystal structure of the firstly obtained molecular salt is precisely identified by employing single-crystal X-ray diffraction and multiple other techniques. The results show that, in the crystal lattice of molecular salt SFM-ATE, the classical hydrogen bonds together with charge-assisted hydrogen bonds contribute to two- dimensional networks, between which the hydrophobic interaction plays an important role. The relevant in vitro/vivo pharmaceutical properties of the dual-drug molecular salt are carried out through a comparative investigation of theoretical and experimental methods. It has been found that SFM displays concurrent improvements over the bulk drug in its permeability and dissolution after forming the molecular salt, which is supported by the molecular electrostatic potential calculation and Hirshfeld surface analysis. Encouragingly, the perfected in vitro biopharmaceutical properties can effectually turn into the in vivo pharmacokinetic preponderances with the expedited peak plasma concentration, lengthened half-life and enhanced bioavailability. Better yet, the antibacterial activities of SFM from the molecular salt get stronger with enlargement in inhibition areas and reduction in values of minimum inhibitory concentrations against the tested bacterial strains. Consequently, the present contribution not only supplies an opportunity for widening applications for classical sulfa drugs via dual-drug salification strategy, but also offers an alternative approach in dealing with viral-bacterial coinfection even other complex diseases by drugs’ hybridization at the molecular level.

The molecular design of drug-ionic liquids for transdermal drug delivery: Mechanistic study of counterions structure on complex formation and skin permeation

Though ionic liquids (ILs) as novel enhancers had garnered wide attention, detailed studies elucidating molecular design of drug-ILs were missing and mechanisms of their formation and skin permeation were still lacking. Herein, we systematically investigated effects of counterions structures on formation and skin permeation of drug-ILs. Firstly, effects of counterions on formation of drug-ILs were dependent on polarizability, molecular weight (M.W.) and polar surface area of counterions. It was caused by strong charge assisted hydrogen bond and van der Waals interactions revealed through FT-IR, X-ray photoelectron spectroscopy and molecular docking, which undermined ionic interactions and reduced total interaction strength, thereby produced lower lattice energy. Then, skin permeability of drug-ILs had a good parabola relationship with M.W., polarizability and log P of counterions. The underlying mechanism was the increased drug miscibility with stratum corneum, which caused conformational disorder and phase transition of lipid bilayers characterized by ATR-FTIR, DSC and confocal laser scanning microscopy. Finally, the drug-ILs proved to be non-irritating using in vivo skin erythema analysis. In conclusion, the quantitative structure-activity relationship models based on counterions structure to predict formation and skin permeation of drug-ILs were developed, which provided basic theory for design of drug-ILs with high permeation-enhancing efficiency.

Mechanically robust amino acid crystals as fiber-optic transducers and wide bandpass filters for optical communication in the near-infrared

Organic crystals are emerging as mechanically compliant, light-weight and chemically versatile alternatives to the commonly used silica and polymer waveguides. However, the previously reported organic crystals were shown to be able to transmit visible light, whereas actual implementation in telecommunication devices requires transparency in the near-infrared spectral range. Here we demonstrate that single crystals of the amino acid L-threonine could be used as optical waveguides and filters with high mechanical and thermal robustness for transduction of signals in the telecommunications range. On their (00bar 1) face, crystals of this material have an extraordinarily high Young’s modulus (40.95 ± 1.03 GPa) and hardness (1.98 ± 0.11 GPa) for an organic crystal. First-principles density functional theory calculations, used in conjunction with analysis of the energy frameworks to correlate the structure with the anisotropy in the Young’s modulus, showed that the high stiffness arises as a consequence of the strong charge-assisted hydrogen bonds between the zwitterions. The crystals have low optical loss in the O, E, S and C bands of the spectrum (1250−1600 nm), while they effectively block infrared light below 1200 nm. This property favors these and possibly other related organic crystals as all-organic fiber-optic waveguides and filters for transduction of information.

Crystal structure of tofacitinib dihydrogen citrate (Xeljanz®), (C16H21N6O)(H2C6H5O7)

The crystal structure of tofacitinib dihydrogen citrate (tofacitinib citrate) has been solved and refined using synchrotron X-ray powder diffraction data, and optimized using density functional techniques. Tofacitinib dihydrogen citrate crystallizes in space group P212121 (#19) with a = 5.91113(1), b = 12.93131(3), c = 30.43499(7) Å, V = 2326.411(6) Å3, and Z = 4. The crystal structure consists of corrugated layers perpendicular to the c-axis. Within the layers, cation⋯anion and anion⋯anion hydrogen bonds link the fragments into a two-dimensional network parallel to the ab-plane. Between the layers, there are only van der Waals contacts. A terminal carboxylic acid group in the citrate anion forms a strong charge-assisted hydrogen bond to the ionized central carboxylate group. The other carboxylic acid acts as a donor to the carbonyl group of the cation. The citrate hydroxy group forms an intramolecular charge-assisted hydrogen bond to the ionized central carboxylate. Two protonated nitrogen atoms in the cation act as donors to the ionized central carboxylate of the anion. These hydrogen bonds form a ring with the graph set symbol R2,2(8). The powder pattern has been submitted to ICDD® for inclusion in the Powder Diffraction File™ (PDF®).

Selective adsorption of ofloxacin and ciprofloxacin from a binary system using lignin-based adsorbents: Quantitative analysis, adsorption mechanisms, and structure-activity relationship

A series of actinia-shaped lignin-based adsorbents (LNAEs) featuring lignin (LN) as the core and grafted poly(acrylic acid) (PAA) as the tentacle were designed and fabricated. Two fluoroquinolones (FQs) with similar molecular structures, ofloxacin (OFL) and ciprofloxacin (CIP), were used as targets to study the selective adsorption performance of LNAEs associated with the structural effects of the LN-based adsorbents in FQs binary aqueous system. The adsorption of the two FQs by LNAEs complied with the competitive Langmuir isothermal model, and showed selective removal of CIP over OFL due to the additional negative charge-assisted hydrogen bond (CAHB) formed between the carboxyl group of LNAEs and the secondary amino group of CIP, in addition to the effects of electrostatic attraction and normal hydrogen bonds, according to quantitative studies and density functional theory analysis. A binary nonlinear model based on phenomenological theory was applied to study the effects of PAA branched-chain length and distribution on the selective adsorption performance of the LN-based adsorbents. Accordingly, the branched-chain distribution played a more important role and higher distribution density of branched PAA could expose more adsorption sites on LNAEs' surface and improve the adsorptive selectivity. This study offers a well understanding of the structure–activity relationship of the surface grafting-modified adsorbents in binary pollutant systems and fundamental guidance for the exploitation and design of novel and efficient adsorbents.

Pharmaceutical salt and salt hydrates of vortioxetine with sulfonic acid to ameliorate the solubility and hygroscopicity via the charge-assisted hydrogen bond assembly

Salt forms of vortioxetine (VOT) with three sulfonic acids have been designed and prepared in 1 : 1 stoichiometry ratio, and their crystal structures and physicochemical properties have also been characterized in detail.

Inspiration for revival of old drugs: improving solubility and avoiding hygroscopicity of pipemidic acid by forming two pharmaceutical salts based on charge-assisted hydrogen bond recognitions

Improving solubility and avoiding hygroscopicity of pipemidic acid by forming pharmaceutical salts based on CAHBs.

Additional Reaction and Mechanism of Dicyanobenzene: Formation of Charge-Assisted Hydrogen Bond Networks

The interaction of LiN(SiMe 3 ) 2 with one equivalent of 1,3- or 1,4-dicyanobenzene followed by the addition of one equivalent of chlorodiphenylphosphine and oxidation by hydrogen peroxide gave charge-assisted hydrogen bond supramolecular polymeric structure compounds of the general formula [ArC(NH 2 ) 2 ] + [Ph 2 PO 2 ] - (Ar = 3-cyanophenyl for 1 , 4-cyanophenyl for 2 ). These compounds, which are composed of a featured type of synthon, show the typical solid-state and film fluorescence. When the above reactions were carried out with half of an equivalent of 1,3-dicyanobenzene, compound 1 and ammonium diphenylphosphinate were produced; with half of an equivalent of 1,4-dicyanobenzene, compound 3 was obtained. A mechanism for the formation of compounds 1-3 was proposed. Results of DFT calculations suggested that the nucleophilic addition reaction to the second cyano group of the dicyanobenzene was a HOMO-controlled process.

Structures of disodium hydrogen citrate mono-hydrate, Na2HC6H5O7(H2O), and di-ammonium sodium citrate, (NH4)2NaC6H5O7, from powder diffraction data.

The crystal structures of disodium hydrogen citrate monohydrate, Na2HC6H5O7(H2O), and di-ammonium sodium citrate, (NH4)2NaC6H5O7, have been solved and refined using laboratory X-ray powder diffraction data, and optimized using density functional techniques. In NaHC6H5O7(H2O), the NaO6 coordination polyhedra share edges, forming zigzag layers lying parallel to the bc plane. The hydro-phobic methyl-ene groups occupy the inter-layer spaces. The carb-oxy-lic acid group makes a strong charge-assisted hydrogen bond to the central carboxyl-ate group. The hydroxyl group makes an intra-molecular hydrogen bond to an ionized terminal carboxyl-ate oxygen atom. Each hydrogen atom of the water mol-ecule acts as a donor, to a terminal carboxyl-ate and the hydroxyl group. Both the Na substructure and the hydrogen bonding differ from those of the known phase Na2HC6H5O7(H2O)1.5. In (NH4)2NaC6H5O7, the NaO6 coordination octa-hedra share corners, making double zigzag chains propagating along the b-axis direction. Each hydrogen atom of the ammonium ions acts as a donor in a discrete N-H⋯O hydrogen bond. The hydroxyl group forms an intra-molecular O-H⋯O hydrogen bond to a terminal carboxyl-ate oxygen atom.

Pharmaceutical salt of tetrahydroberberine with sulfamic acid prepared via CAHBs

In order to further explore the role of Charge-assisted hydrogen bonds (CAHBs) recognition in the formation of tetrahydroberberine (THB) pharmaceutical salt/cocrystal, based on the analysis of the molecular interactions in forming unit pharmaceutical salts/cocrystal of THB and sulfophenyl acids, we speculate that hydroxyl group of sulfamic acid (SA) may cocrystallize with N atom on the quinoline ring of THB via CAHBs. Consequently, an unreported pharmaceutical salt (C20H22NO4·NH2SO3, THB-SA) of the THB was designed and synthesized. The THB-SA was characterized by single crystal X-ray diffraction, XRPD and TG methods. As expected, structure analysis of the THB-SA revealed that the THB molecule binds to the SA molecule precisely through CAHBs (N+-H···O−) between the N atom on the quinoline ring and sulfonic acid group of SA in asymmetric unit of THB-SA. This successfully implemented work implies that in the preparation of THB pharmaceutical salts/cocrystals, cocrystal formers (CCFs) that can form CAHBs with THB should be selected, which will provide a facilitate way to prepare THB pharmaceutical salts/cocrystals.

Crystal structures of two isostructural compounds: a second polymorph of dipotassium hydrogen citrate, K2HC6H5O7, and potassium rubidium hydrogen citrate, KRbHC6H5O7.

The crystal structures of a new polymorph of dipotassium hydrogen citrate, 2K+·HC6H5O72-, and potassium rubidium hydrogen citrate, K+·Rb+·HC6H5O72-, have been solved and refined using laboratory powder X-ray diffraction and optimized using density functional techniques. In the new polymorph of the dipotassium salt, KO7 and KO8 coordination polyhedra share corners and edges to form a three-dimensional framework with channels parallel to the a axis and [111]. The hydrophobic methylene groups face each other in the channels. The un-ionized carboxylic acid group forms a strong charge-assisted hydrogen bond to the central ionized carboxylate group. The hydroxy group forms an intermolecular hydrogen bond to a different central carboxylate group. In the potassium rubidium salt, the K+ and Rb+ cations are disordered over two sites, in approximately 0.72:0.28 and 0.28:0.72 ratios. KO8 and RbO9 coordination polyhedra share corners and edges to form a three-dimensional framework with channels parallel to the a axis. The un-ionized carboxylic acid group forms a strong charge-assisted hydrogen bond to an ionized carboxylate group. The hydroxy group forms an intermolecular hydrogen bond to the central carboxylate group. Density functional theory (DFT) calculations on the ordered cation structures suggest that interchange of K+ and Rb+ at the two cation sites changes the energy insignificantly.

Evaluation of charge assisted hydrogen bonds in L-(S)-lysinium L-(S)-mandelate dihydrate and L-(S)-alanine L-(S)-mandelic acid complexes: Inputs from Hirshfeld surface, PIXEL energy and QTAIM analysis

Single crystals of two of the l-amino acids (lysine and alanine) complexed with L-mandelic acids are prepared by slow evaporation technique and X-ray diffraction analysis has been carried out. Single crystal X-ray analysis reveals that lysine-mandelic acid crystallized as a dihydrate form. In the crystalline state, the lysine molecule exists in the cationic form in which the backbone and side chain amino groups are protonated and the carboxylic acid is deprotonated. The carboxylic acid proton of the mandelic acid is transferred to the lysine side chain and thus carries a negatively charged ion. The lattice water molecules are located near the amino groups of the lysine. In contrast, alanine molecule exists in the zwitterionic form in which amino group is protonated and carboxylic acid is deprotonated and the mandelic acid is in the neutral form in the re-determined alanine-mandelic acid complex. Crystal packing of lysine-mandelate and alanine-mandelic acid complexes is qualitatively analyzed using Hirshfeld surfaces and 2D-fingerprint plots. The energetics of different dimeric pairs observed in complexes is quantitatively analyzed using PIXEL energy analysis. Topological parameters derived from QTAIM framework are used to delineate the nature of different intermolecular interactions formed in lysine/alanine-mandelic acid complexes. In this work, we used IQA scheme to evaluate the strength of charged assisted hydrogen bonds in the title complexes.

Characterization and adsorption performance of biochars derived from three key biomass constituents

The effects of biomass constituents on biochar adsorption performance are still unclear. In this work, three main biomass constituents, lignin, cellulose and xylan (hemicellulose), were converted into biochar. These biochars showed obvious differences, which were observed by physicochemical characteristics analysis. Based on the acid-base titration, the contents of functional groups on different biochars decreased as lignin > hemicellulose > cellulose. The findings from elemental analyses showed that the degree of lignin pyrolysis was lower than cellulose and hemicellulose; however, lignin biochar had the highest yield and ash content. The scanning electron micrographs demonstrated that both lignin and xylan biochars were similarly spherical, while cellulose biochar was fibrous. Furthermore, the sulfadimidine (SMT) adsorption experiments revealed that physicochemical characteristics of biochars obviously affected the adsorption behavior. Cellulose and xylan biochars indicated similar pH-dependent sorption patterns, but the latter exhibited higher adsorption capacity. In contrast, lignin biochar had no adsorption capacity due to the high ash content. The adsorption was dominated by the electrostatic repulsion, EDA interactions, hydrogen bonds and negative charge-assisted hydrogen-bond. Overall, these observations are of significant importance for guiding in the selection of feedstock used for biochar preparation and predicting the sorption behavior of SMT on biochars.

Structure of Imidazolium-N-phthalolylglycinate Salt Hydrate: Combined Experimental and Quantum Chemical Calculations Studies

An organic supramolecular salt hydrate (imidazolium:N-phthalolylglycinate:H2O; IM+-NPG−-HYD) has been examined for its charge-transfer (CT) characteristics. Accordingly, IM+–NPG−–HYD has been characterized thoroughly using various spectroscopic techniques. Combined experimental and quantum chemical studies, along with wave function analysis, were performed to study the non-covalent interactions and their role in CT in the supramolecular salt hydrate. Notably, IM+–NPG−–HYD crystalizes in two configurations (A and B), both of which are held together via non-covalent interactions to result in a three-dimensional CT supramolecular assembly. The through-space CT occurs from NPG– (donor) to IM+ (acceptor), and this was mediated via non-covalent forces. We demonstrated the role of π–π stacking interactions (mixed-stacking donor-acceptor interactions) in the presence of charge-assisted hydrogen bonds in the regulation of CT properties in the self-assembly of the IM+–NPG−–HYD salt hydrate.

Charge-Assisted Hydrogen Bonds in Self-Assemblies of Small Molecules: Visu-al Detection and Prospects

Charge-Assisted Hydrogen Bonds in Self-Assemblies of Small Molecules: Visu-al Detection and Prospects

Charge-assisted hydrogen bond and nitrile⋯nitrile interaction directed supramolecular associations in Cu(ii) and Mn(ii) coordination complexes: anticancer, hematotoxicity and theoretical studies

Charge-assisted H-bonds and nitrile⋯nitrile interactions directed assemblies in Cu(ii) and Mn(ii) complexes have been analyzed by MEP surface and NCI plot index. Anticancer activities and hematotoxictiy have been investigated.

Effect of Charge-Assisted Hydrogen Bonds on Single-Molecule Electron Transport

The effect of the in-backbone presence of charge-assisted hydrogen bonds (CAHBs) in the conductance of single-molecule junctions has been studied by the scanning tunneling microscope break junction technique. In particular, two amidinium–carboxylate supramolecular complexes of different lengths have been tested. We observed that the ionic character that gives extra stability to the CAHB is a hindrance toward the electron transport through the complexes. Theoretical calculations using the DFT + Σ method indicate that both the highest occupied molecular orbital and lowest unoccupied molecular orbital of the complexes are fully localized in only one of the moieties of the complex explaining the low single-molecular conductance of the compounds.

Open Pentiptycene Networks Assembled through Charge-Assisted Hydrogen Bonds

A series of hydrogen-bonded networks was prepared incorporating ditopic, tritopic, or tetratopic polyamidinium tectons and linear pentiptycene dicarboxylates. The ditopic amidinium forms a 1D hydro...

Tetrahydroberberine pharmaceutical salts/cocrystals with dicarboxylic acids: Charge-assisted hydrogen bond recognitions and solubility regulation

With our consistent aim to further expand the solid-state landscape via molecular recognition and regulate solubility of tetrahydroberberine (THB), charge-assisted hydrogen bond (CAHB) recognitions and solubility regulation of pharmaceutical salts/cocrystals of THB are comprehensively investigated through exploring four pharmaceutical salts/cocrystals of THB. Four pharmaceutical salts/cocrystals of THB with oxalic acid, malonic acid, maleic acid and fumaric acid were obtained with solution evaporation approach. Comprehensive crystal structures and Hirshfeld surface analyses reveal CAHB recognitions between THBs and coformers are dominant intermolecular interactions to stabilize crystal packing. As expected, solubilities of four pharmaceutical salts/cocrystals of THB have been improved by dicarboxylic acids. Importantly, the dicarboxylic acid with higher solubility can modulate solubility of THB to become higher. The enthalpy of hydration for four pharmaceutical salts/cocrystals is greater than that for neutral pure THB when CAHBs (with electrostatic interactions) exist, which effectively improve solubility of THB. Solvent molecules can disrupt interactions of pharmaceutical salts/cocrystals by solvent···solute interactions when dicarboxylic acids are highly soluble thereby leading to enhancement of dissolution. Research results inspirationally enlightens that the solubility of insoluble APIs could be effectively regulated by utilizing gradient solubility coformers with simultaneously forming CAHBs between active pharmaceutical ingredients and coformers.

Low-Barrier Hydrogen Bonds in Negative Thermal Expansion Material H3 [Co(CN)6

The covalent nature of the low-barrier N-H-N hydrogen bonds in the negative thermal expansion material H3 [Co(CN)6 ] has been established by using a combination of X-ray and neutron diffraction electron density analysis and theoretical calculations. This finding explains why negative thermal expansion can occur in a material not commonly considered to be built from rigid linkers. The pertinent hydrogen atom is located symmetrically between two nitrogen atoms in a double-well potential with hydrogen above the barrier for proton transfer, thus forming a low-barrier hydrogen bond. Hydrogen is covalently bonded to the two nitrogen atoms, which is the first experimentally confirmed covalent hydrogen bond in a network structure. Source function calculations established that the present N-H-N hydrogen bond follows the trends observed for negatively charge-assisted hydrogen bonds and low-barrier hydrogen bonds previously established for O-H-O hydrogen bonds. The bonding between the cobalt and cyanide ligands was found to be a typical donor-acceptor bond involving a high-field ligand and a transition metal in a low-spin configuration.