Cocrystallization-Driven Double-Optimized Stratagem toward Directional Self-Assembly for the First Ternary Salt Cocrystal of Cardiotonic Drug Milrinone with Different Phenolic Acids Exhibits Optimal In Vitro/Vivo Biopharmaceutical Peculiarities.

The current research leverages the structural features and property superiorities along with benefits in protecting cardiovascular system of gallic acid (GLC) and gentisic acid (HGA) to optimize in vitro/vivo peculiarities of cardiotonic drug milrinone (MIL) through developing a stratagem of cocrystallization-driven double-optimized ternary salt cocrystal. This strategy assembles MIL ternary salt cocrystal by shaping a cocrystallization moiety relying on noncovalent interplays with GLC to obtain permeability advancement and molding a salt segment via the salification of proton transfer between HGA and MIL molecules to facilitate solubility enhancement. While the ameliorative in vitro properties further modulate the in vivo pharmacokinetic behaviors, thus fulfilling a dual optimization of MIL's biopharmaceutical characteristics on both in vitro and in vivo aspects. Along this line, the first MIL ternary salt cocrystal, viz., [HMIL+-GA-]-MIL-GLC-H2O (denoted as MTSC hereinafter), has been satisfactorily constructed and precisely structurally identified by diversified techniques. The single-crystal X-ray diffraction experiment validates that a molecular salt [HMIL+-GA-] species cocrystallizes with one neutral MIL, two GLC, and five solvent water molecules, among which the organic constituents compose laminated hydrogen bond networks, and then are self-assembled by water molecules to a 3D supramolecular structure. The unique structural feature and stacking pattern of MTSC make both the permeability and solubility be respectively enhanced by 9.69 times and 5.17- to 6.03-fold compared with the parent drug per se. The experimental outcomes are powerfully supported by associated calculations based on density functional theory. Intriguingly, these optimal in vitro physicochemical natures of MTSC have been potently converted into strengths of in vivo pharmacokinetics, showcasing the elevated drug plasma concentration, elongated half-life, alongside advanced bioavailability. Consequently, this presentation not just contributes a brand-new crystalline form with utility values, but ushers in a new dimension of ternary salt cocrystals for improving in vitro/vivo limitations of poor drug bioavailability.

Correction: Supramolecular self-assembly of amantadine hydrochloride with ferulic acid via dual optimization strategy establishes a precedent of synergistic antiviral drug-phenolic acid nutraceutical cocrystal.

Correction for 'Supramolecular self-assembly of amantadine hydrochloride with ferulic acid via dual optimization strategy establishes a precedent of synergistic antiviral drug-phenolic acid nutraceutical cocrystal' by Ling-Yang Wang et al., Analyst, 2021, 146, 3988-3999, https://doi.org/10.1039/D1AN00478F.

Supramolecular self-assembly of amantadine hydrochloride with ferulic acid via dual optimization strategy establishes a precedent of synergistic antiviral drug-phenolic acid nutraceutical cocrystal.

To display the capability of the phenolic acid nutraceutical ferulic acid (FLA) in optimizing the in vitro/in vivo properties of the antiviral drug amantadine hydrochloride (AMH) and achieve synergistically enhanced antiviral effects, thereby gaining some new insights into pharmaceutical cocrystals of antiviral drugs with phenolic acid nutraceuticals, a cocrystallization strategy of dual optimization was created. Based on this strategy, the first drug-phenolic acid nutraceutical cocrystal of AMH with FLA, namely AMH-FLA-H2O, was successfully assembled and completely characterized by employing single-crystal X-ray diffraction and other analytical techniques. The cocrystal was revealed to be composed of AMH, FLA, and water molecules in the ratio of 3 : 1 : 1.5, and charge-assisted hydrogen bonds containing chloride ions crucially maintained the crystal lattice together with water molecules. The in vitro/in vivo properties of the cocrystal were systematically evaluated via both theoretical and experimental methods, and the results indicate that the dissolubility of AMH is down-regulated by two-thirds in the cocrystal, resulting in its potential for sustained pharmacokinetic release and the elimination of the adverse effects of AMH. More importantly, the enhanced antiviral effects of the current cocrystal were proven against four viral strains, and the pharmaceutical synergy between AMH and FLA was realized with a combination index (CI) of less than 1. Thus, the present work provides a novel crystalline product with bright commercial prospect for the classical antiviral drug AMH and also establishes an avenue for the synergetic antiviral application of nutraceutical phenolic acids via the cocrystallization strategy of dual optimization.

Supramolecular self-assembly and perfected in vitro/vivo property of 5-fluorouracil and ferulic acid on the strength of double optimized strategy: the first 5-fluorouracial-phenolic acid nutraceutical cocrystal with synergistic antitumor efficacy.

For highlighting the predominance of phenolic acid nutraceutical ferulic acid (FR) in regulating the in vivo/vitro performances of anticancer drug 5-fluorouracil (Flu) and strengthening their cooperativity in antitumor effect, thus achieving a major breakthrough in the development of drug-nutraceutical cocrystal with synergistic antitumor action, a cocrystallization strategy of dual optimization is created, in which both the in vivo and vitro natures of Flu are improved by exploiting the FR's excellent physicochemical property. Moreover, Flu's anticancer effects were promoted by exerting the assistant antitumor peculiarity of FR. Such dual optimization of FR for Flu in physicochemical properties and anticancer activities is beneficial for realizing synergistic augmentation effect by taking the benefit of the cooperativeness of Flu and FR in the anticancer ability. Based on this idea, a novel cocrystal of Flu and FR, namely, Flu-FR-H2O, is successfully assembled as the first 5-fluorouracil-nutraceutical cocrystal with synergistic antitumor effect and its explicit structure is resolved. The single-crystal X-ray diffraction demonstrates that Flu and FR have a ratio of 1 : 1 with one equivalent of solvent water in the cocrystal, where one-dimensional hydrogen-bonding helices and FR-Flu hydrogen-bonding pairs, together construct a three-dimensional supramolecular network. By combining experimental evaluation with theoretical analysis, in vitro/vivo pharmaceutical properties are scientifically investigated. Results show that the permeability and aqueous solubility of Flu are respectively elevated by 5.08 and 1.64 folds, which has brought about ameliorated pharmacokinetics, thus providing prolonged retention time and increased oral bioavailability. More interestingly, the cocrystal shows synergistic inhibition ability of Flu and FR against tested tumor cell strains, hence laying the groundwork for reducing the dosage and even the toxic side effects of Flu. As a result of this, the present research not only provides a new strategy for Flu to optimize its physicochemical properties and antitumor activities simultaneously but also offers some opinions for the development of synergistic antitumor pharmaceutical cocrystals.

Cocrystallization with syringic acid presents a new opportunity for effectively reducing the hepatotoxicity of isoniazid.

Objective: With the aim of surmounting the severe hepatotoxicity induced by antituberculosis drug isoniazid (INH), a novel cocrystal of INH with hepatoprotective nutraceutical syringic acid (SYA), namely INH-SYA, was designed and prepared through cocrystallization strategy, which is an intriguing attempt to reduce the toxic side effects of INH.Significance: The study not only provides new thinking for inhibiting toxic side effects of drugs through cocrystallization strategy, but also opens a new pathway for the application of nutraceuticals in the pharmacy.Methods: INH and SYA were successfully crystallized into the same crystal lattice through combining volatilization with solvent assisted methods. The resulting cocrystal was structurally characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC).Results: The SCXRD analysis for the present cocrystal revealed that it has a 1:1 ratio of INH to SYA with two molecules INH homodimers and two SYA molecules, in which they are arranged alternately linked by hydrogen bonds to form a six molecules ring structure (R66(40)) in crystal. The systematic evaluation of the in vitro/in vivo suggested that, owing to the formation of cocrystal, the dissolution efficiency of SYA was increased 5.85-fold compared with that of coarse SYA, and the oral bioavailability of the cocrystal in rats was enhanced by 3.66 times. As a result, the present INH-SYA cocrystal almost removed INH induced serious hepatotoxicity, which was further demonstrated by the hepatotoxicity studies in rats.Conclusion: INH-SYA cocrystal could effectively reduce the hepatotoxicity of INH.

Synthesis, structure, and biological active evaluation of a new cyclic tetranuclear copper(II) complex bridged both by oxamido and carboxylate groups.

A new tetracopper(II) complex bridged both by oxamido and carboxylato groups, namely [Cu4 (dmaepox)2 (bpy)2 ](NO3 )2 ·2H2 O, where H3 dmaepox and bpy represent N-benzoato-N'- (3-methylaminopropyl)oxamide and 2,2'-bipyridine, was synthesized, and its structure reveals the presence of a centrosymmetric cyclic tetracopper(II) cation assembled by a pair of cis-dmaepox3- - bridged dicopper(II) units through the carboxylato groups, in which the endo- and exo-copper(II) ions bridged by the oxamido group have a square-planar and a square-pyramidal coordination geometries, respectively. The aromatic packing interactions assemble the complex molecules to a two-dimensional supramolecular structure. The reactivity toward DNA and protein bovine serum albumin (BSA) indicates that the complex can interact with herring sperm DNA through the intercalation mode and the binding affinity is dominated by the hydrophobicity and chelate ring arrangement around copper(II) ions and quenches the intrinsic fluorescence of BSA via a static process. The cytotoxicity of the complex shows selective cancer cell antiproliferative activity.

Synthesis and structure of a new trinuclear nickel(II) complex bridged by N-[3-(Dimethylamino)propyl]-N'-(2-hydroxyphenyl)oxamido: in vitro anticancer activities, and reactivities toward DNA and protein.

A new trinickel(II) complex bridged by N-[3-(dimethylamino)propyl]- N'-(2-hydroxylphenyl)oxamido (H3 pdmapo), namely [Ni3 (pdmapo)2 (H2 O)2 ]⋅4CH3 OH, was synthesized and characterized by X-ray single-crystal diffraction and other methods. In the molecule, two symmetric cis-pdmapo3- mononickel(II) complexes as a "complex ligand" using the carbonyl oxygen atoms coordinate to the center nickel(II) ion situated on an inversion point. The Ni···Ni distance through the oxamido bridge is 5.2624(4) Å. The center nickel(II) ion and the lateral ones have octahedral and square-planar coordination geometries, respectively. In the crystal, a three-dimensional supramolecular network dominated by hydrogen bonds is observed. The reactivity toward DNA/protein bovine serum albumin (BSA) revealed that the complex could interact with herring sperm DNA (HS-DNA) through the intercalation mode and quench the intrinsic fluorescence of BSA via a static mechanism. The in vitro anticancer activities suggested that the complex is active against the selected tumor cell lines.

Synthesis, structure, and biological activities of a new µ-oxamido-bridged dicopper(II) complex: the influence of hydrophobicity of bridging ligand on DNA binding and cytotoxic activities.

A new µ-oxamido-bridged dicopper(II) complex, [Cu2 (papo)(H2 O)- (phen)]Cl·CH3 OH·H2 O, where H3 papo and phen represent N-(2-hydroxyphenyl)-N'-(3-aminopropyl)oxamide and 1,10-phenanthroline, respectively, has been synthesized and characterized by elemental analysis, molar conductivity measurement, infrared and electronic spectra studies, and single-crystal X-ray diffraction. The complex crystallizes in the triclinic space group P-1. Each copper(II) ion is located in a slightly distorted square-pyramidal environment. The Cu···Cu distance through the oxamide bridge is 5.1848(7) Å. The three-dimensional supramolecular structure is built-up by hydrogen bonds and π-π stacking interactions. The dicopper(II) complex exhibits cytotoxic activity against the SMMC-7721 and A549 cell lines. The reactivity toward herring sperm DNA and protein bovine serum albumin (BSA) reveals that the dicopper(II) complex can interact with the DNA by the intercalation mode, and effectively quench the intrinsic fluorescence of BSA via a static mechanism. The influence of hydrophobicity of the bridging ligand on DNA-binding properties and in vitro cytotoxic activities of this kind of dicopper(II) complexes was investigated.

Synthesis and Structure of a New Copper(II) Coordination Polymer Alternately Bridged by Oxamido and Carboxylate Groups: Evaluation of DNA/BSA Binding and Cytotoxic Activities.

A new one-dimensional (1D) copper(II) coordination polymer {[Cu2 (dmaepox)(dabt)](NO3) · 0.5 H2 O}n , where H3 dmaepox and dabt denote N-benzoato-N'-(3-methylaminopropyl)oxamide and 2,2'-diamino-4,4'-bithiazole, respectively, was synthesized and characterized by single-crystal X-ray diffraction and other methods. The crystal structure analysis revealed that the two copper(II) ions are bridged alternately by cis-oxamido and carboxylato groups to form a 1-D coordination polymer with the corresponding Cu · · · Cu separations of 5.1946(19) and 5.038(2) Å. There is a three-dimensional supramolecular structure constructed by hydrogen bonding and π-π stacking interactions in the crystal. The reactivity towards herring sperm DNA (HS-DNA) and bovine serum albumin (BSA) indicated that the copper(II) polymer can interact with the DNA in the mode of intercalation, and bind to BSA responsible for quenching of tryptophan fluorescence by the static quenching mechanism. The in vitro cytotoxicity suggested that the copper(II) polymer exhibits cytotoxic effects against the selected tumor cell lines.

Synthesis and Structure of a Ternary Copper(II) Complex with Mixed Ligands of Diethylenetriamine and Picrate: DNA/Protein-Binding Property and In Vitro Anticancer Activity Studies.

Based on the importance of the design and synthesis of transition metal complexes with noncovalent DNA/protein-binding abilities in the field of metallo pharmaceuticals, a new mononuclear ternary copper(II) complex with mixed ligands of diethylenetriamine (dien) and picrate anion (pic), identified as [Cu(dien)(pic)](pic), was synthesized and characterized by elemental analysis, molar conductivity measurement, infrared spectrum, electronic spectral studies, and single-crystal X-ray diffractometry. The structure analysis reveals that the copper(II) complex crystallizes in the monoclinic space group P21 /c, and the copper(II) ion has a distorted square pyramidal coordination geometry. A two-dimensional supramolecular structure is formed through hydrogen bonds. The DNA/bovine serum albumin (BSA)-binding properties of the complex are explored, indicating that the complex can interact with herring sperm DNA via intercalation mode and bind to BSA responsible for quenching of tryptophan fluorescence by static quenching mechanism. The in vitro anticancer activity shows that the copper(II) complex is active against the selected tumor cell lines.

In vitro cytotoxic activities, DNA-, and BSA-binding studies of a new dinuclear copper(II) complex with N-[3-(dimethylamino)propyl]-N'-(2-carboxylatophenyl)-oxamide as ligand.

A new dinuclear copper(II) complex bridged by N-[3-(dimethylamino)propyl]-N'- (2-carbo-xylatophenyl)oxamide (H3 dmapob), and endcapped with 2,2'-diamino-4,4'-bithiazole (dabt), namely [Cu2(dmapob)(dabt)(CH3OH)(pic)]·(DMF)0.75 ·(CH3OH)0.25 has been synthesized and characterized by elemental analysis, molar conductivity measurement, infrared and electronic spectra studies, and single-crystal X-ray diffraction. In the crystal structure, both copper(II) ions have square-pyramidal coordination geometries. The Cu···Cu separation through the oxamido bridge is 5.176(9) Å. A two-dimensional supramolecular framework is formed through hydrogen bonds and π-π stacking interactions. The reactivities toward herring sperm DNA and bovine serum albumin (BSA) show that the complex can interact with the DNA via intercalation mode and bind to the BSA responsible for quenching of tryptophan fluorescence by the static quenching mechanism. The in vitro anticancer activities suggest that the copper(II) complex is active against the selected tumor cell lines. The influence of different bridging ligands in dinuclear complexes on the DNA- and BSA-binding properties as well as anticancer activities is preliminarily discussed.

Synthesis and crystal structure of binuclear copper(II) complex bridged by N-(2-hydroxyphenyl)-N'-[3-(diethylamino)propyl]oxamide: in vitro anticancer activity and reactivity toward DNA and protein.

A new oxamido-bridged bicopper(II) complex, [Cu2(pdpox)(bpy)(CH3OH)](ClO4), where H3pdpox and bpy stand for N-(2-hydroxyphenyl)-N'-[3-(diethylamino)propyl]oxamide and 2,2'-bipyridine, respectively, has been synthesized and characterized by elemental analyses, molar conductivity measurements, infrared and electronic spectra studies, and X-ray single crystal diffraction. In the crystal structure, the pdpox(3-) ligand bridges two copper(II) ions as cisoid conformation. The inner copper(II) ion has a {N3O} square-planar coordination geometry, while the exo- one is in a {N2O3} square-pyramidal environment. There are two sets of interpenetrating two-dimensional hydrogen bonding networks parallel to the planes (2 1 0) and (21¯0), respectively, to form a three-dimensional supramolecular structure. The bicopper(II) complex exhibits cytotoxic activity against the SMMC7721 and A549 cell lines. The reactivity toward herring sperm DNA and bovine serum albumin revealed that the bicopper(II) complex can interact with the DNA by intercalation mode, and the complex binds to protein BSA responsible for quenching of tryptophan fluorescence by static quenching mechanism.

The first nano-cocrystal formulation of marine drug cytarabine with uracil based on cocrystal nanonization strategy for long-acting injection exhibiting enhanced antitumor activity.

To emphasize the superiority of uracil (UR) in ameliorating biopharmaceutical characteristics of marine antitumor medicine cytarabine (ARA), thus gaining some innovative opinions for the exploitation of nanococrystal formulation, a cocrystal nanonization strategy is proposed by integrating cocrystallization and nanosize preparation techniques. For one thing, based on UR's unique structural features and natures together with advantages of preferential uptake by tumor cells, cocrystallizing ARA with UR is expected to improve the in vitro/vivo performances. For another, the nanonization procedure is oriented towards maintaining the long-term effective drug level. Along this route, a cocrystal of ARA with UR, viz., ARA-UR, is successfully synthesized and then transformed into nano-cocrystal. The cocrystal structure is precisely confirmed by various methods, demonstrating that a 1:1 ARA and UR in the crystal forms cytosine-UR hydrogen-bonding interactions, thus constructing supramolecular frameworks by strong π-π stacking interplays; while the nano-cocrystal is block-shaped particles of 562.70 nm with zeta potential -33.40 mV. The properties of cocrystal ARA-UR and its nano-cocrystal in vitro/vivo are comparatively explored by theoretical calculations and experimental analyses, revealing that permeability of both is significantly increased than ARA per se. Notably, the meliorative natures of both the cocrystal and nano-cocrystal in vitro bring excellent antitumor activity, but the latter has greater strengths over the former. More notably, the nano-cocrystal can sustain effective concentration for a relatively longer time, causing lengthened retention time and better absorption in vivo. The contribution offers a fire-new dosage form of ARA for long-lasting delivery, thus filling the vacancy in nanococrystal studies about marine drugs.

A novice cocrystal nanomicelle formulation of 5-fluorouracil with proline: The design, self-assembly and in vitro/vivo biopharmaceutical characteristics.

To fully play the advantages of cocrystallization and nano-preparation techniques in regulating in vitro/vivo biopharmaceutical properties of anticancer drug 5-fluorouracil (FU), and further exploit new avenues in its formulation development, a recombination strategy of cocrystallization and nano-micellar self-assembly techniques is proposed. Thereinto, the cocrystallization technique is aiming at augmenting antitumor ability by ameliorating physicochemical performances of FU, while the nano-micellar self-assembly technique is mainly employed to achieve slowed release and long-term efficacy. Guided by this strategy, a new zwitterionic cocrystal of FU with L-proline (PL), FU-PL, is successfully synthesized, and then incorporated into carriers PEG-PCL to gain cocrystal micelles. The structure of FU-PL cocrystal and morphology of the cocrystal micelles are respectively characterized via various analytical means. The comparative studies of in vivo/vitro properties are systematacially conducted by theoretical and experimental methods. The results showcase that the cocrystal's solubility and permeability are 4.60 and 3.89 folds higher than those of pristine drug FU at pH 6.8, separately; and the drug loading and entrapment efficiency of the obtained cocrystal micelles with spherical particles of 146 nm are 2.39 and 1.74 times than those of FU micelles itself, respectively. Particularly, both the cocrystal and its micelles eventually bring about the excellent antitumor activity, but the cocrystal micelles improve even more significantly in comparison with the cocrystal. These in vitro advantages have promoted the in vivo absorption with increased relative bioavailability (FREL) of 2.72 relative to FU-PL cocrystal. More particularly, the cocrystal micelles have preferable sustained-release action relative to FU micelles, thus more efficaciously prolonging the half-life and therapy duration. All these findings not only supply a novice slow-release dosage form for FU with greater efficiency, but also fill the blank of the micelle researches for antitumor pharmaceutical cocrystals.

The first marine dual-drug cocrystal of cytarabine with 5-fluorouracil having synergistic antitumor effects shows superior biopharmaceutical peculiarities by oral administration.

In order to highlight the advantages of cocrystallization technique in perfecting in vitro/vivo natures of marine drug cytarabine (ARC), and fill the gap of the research of marine pharmaceutical cocrystals with synergistic antitumor effects, the first dual-drug cocrystal simultaneously containing ARC and antitumor drug 5-fluorouracil (FU), viz. ARC-FU, is successfully designed and assembled. The accurate structure is perfectly resolved by single-crystal X-ray diffraction and other approaches. The analytical outcomes demonstrate that the codrug cocrystal consists of ARC and FU with a molar ratio of 1:1, in which FU molecule plays an important role by participating in the formation of both "pyrimidine-pyrimidine" and "pyrimidine-sugar" cyclic hydrogen-bonding systems with ARC molecules. In the cocrystal, there are twofold hydrogen-bonding helixes of ARC molecules and a whole three-dimensional hydrogen-bonding network which also contains the aromatic stacking interaction between pyrimidine rings of both components. Such structural feature and aggregation model have crucial influences on the improvements of in vitro/vivo properties, which is methodically verified by the combination of theoretical analyses and experimental measurements. The in vitro studies exhibit the suitably reduced solubility and obviously increased permeability for the cocrystal that is in accord with the theoretical prediction. Importantly, the ameliorated in vitro peculiarities realize in vivo pharmacokinetic optimization including the extended residence time and enhanced relative bioavailability. Of greater significance, ARC exerts synergistic antitumor effects in association with FU that brings about potentiation of cell growth inhibition with lower IC50. Thus, this research not only provides a novel crystalline form for ARC with forward-looking development value, but also breaks new ground for the development of synergistic antitumor pharmaceutical cocrystals with marine characteristics.

5-fluorouracil-caffeic acid cocrystal delivery agent with long-term and synergistic high-performance antitumor effects.

Aim: To explore how to transform cocrystals of the anticancer drug 5-fluorouracil (FL) with caffeic acid (CF; FL-CF-2H2O) into a nanoformulation, a self-assembly strategy of cocrystal-loaded micelles is proposed. Methods: Nanomicelles were assembled to deliver cocrystal FL-CF-2H2O with synergistic activity, and their in vitro/vivo properties were evaluated by combining theoretical and experimental methods. Result: More cocrystal was packed into the polymers due to the stronger interaction energy during micellar assembly, producing excellent cytotoxicity and pharmacokinetic behavior, especially synergistic abilities and long-term therapy. Conclusion: This case exemplifies the particular benefits of the self-assembly strategy of cocrystal-loaded micelles in keeping a delicate balance between long-term effects and high efficiency for FL, and offers a feasible technical scheme for cocrystal delivery agents for antitumor drugs.

To exemplify the feasibility of the cocrystal conversion of anticancer drug 5-fluorouracil (FL) with phenolic acid nutrient caffeic acid (CF) into a nanomicelle formulation, and further provide new options for the development of slowed-release cocrystal formulations with long-acting and synergistic antitumor effects, in this study, a cocrystalline complex of FL and CF (cocrystal FL-CF-2H₂O) was loaded into polymer PEG-PCL to successfully assemble the cocrystal nanomicelles by a self-assembly strategy. The morphology of the cocrystal nanomicelles was characterized, and in vitro/vivo properties were evaluated by combining theoretical with experimental methods. The results showed that the cocrystal nanomicelles with regular sphericity and homogeneous particle size had greater drug loading and entrapment efficiency than FL nanomicelles, which is also supported by theoretical predictions of the interaction energy between the cocrystal FL-CF-2H₂O and polymer PEG-PCL. The excellent encapsulation effects give rise to more potent cytotoxicity, better absorption and prolonged retention time in vivo. Relative to FL nanomicelles, the present cocrystal nanomicelles with synergistic antitumor abilities exhibited prominent slowed-release behavior that was more conducive to the long-term maintenance of therapeutic concentrations in vivo. The present case offers a feasible technical scheme for successful nanoformulation research on synergistic antitumor pharmaceutical cocrystals.

(Aqua-2κO)bis(2,2'-bipyridine-1κ2N,N'){µ-N-[3-(dimethylamino)propyl]-N'-(2-oxidophenyl)oxamidato(3-)-1:2κ2O,O':κ4O'',N,N',N''}copper(II)nickel(II) perchlorate.

The title complex, [CuNi(C(13)H(16)N(3)O(3))(C(10)H(8)N(2))(2)(H(2)O)]ClO(4), has a cis-oxamide-bridged heterobinuclear cation, with a Cu···Ni separation of 5.3297 (6) Å, counterbalanced by a disordered perchlorate anion. The Cu(II) and Ni(II) cations are located in square-pyramidal and octahedral coordination environments, respectively. The complex molecules are assembled into a three-dimensional supramolecular structure through hydrogen bonds and π-π stacking interactions. The influence of the two types of metal cation on the supramolecular structure is discussed.

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.

Tetrakis(2,2'-bipyridine)-1kappa(4)N,N';4kappa(4)N,N'-{mu4-N,N'-bis[3-(2-oxidoethylamino)propyl]oxamidato(4-)-1:2:3:4kappaO:kappa(3)N,N',O':kappa(3)O'',N'',N''':kappaO'''}tetracopper(II) tetrakis(perchlorate).

The title complex, [Cu(4)(C(12)H(22)N(4)O(4))(C(10)H(8)N(2))(4)](ClO(4))(4), has a novel tetranuclear copper(II) cation with the oxamidate and ethanolate groups of a trans tetraanion of N,N'-bis[3-(hydroxyethylamino)propyl]oxamide (H(4)heap) as bridges. The Cu...Cu separation through the oxamide group is 5.1592 (15) A, while those through the two ethanolate bridges are 3.3845 (13) and 3.3392 (13) A. The two central copper(II) ions are in square-planar N(2)O(2) environments, while the two terminal copper(II) ions have distorted N(4)O square-pyramidal geometries. The heap(4-) ligand, with an iminoalcohol form, has both an oxamide and two ethanolate bridges. Two of the four perchlorate anions are disordered and have long contacts with the square-planar Cu(II) ions. The three-dimensional structure features arene-perchlorate C-H...O hydrogen bonds and pi-pi stacking.

catena-Poly[[(2,2'-diamino-4,4'-bithiazole){µ3-cis-N-(2-carboxylatophenyl)-N'-[3-(dimethylamino)propyl]oxamidato(3-)}dicopper(II)] nitrate 0.6-hydrate].

The title complex, {[Cu(2)(C(14)H(16)N(3)O(4))(C(6)H(6)N(4)S(2))]NO(3)·0.6H(2)O}(n), is a one-dimensional copper(II) coordination polymer bridged by cis-oxamide and carboxylate groups. The asymmetric unit is composed of a dinuclear copper(II) cation, [Cu(2)(dmapob)(dabt)](+) {dmapob is N-(2-carboxylatophenyl)-N'-[3-(dimethylamino)propyl]oxamidate and dabt is 2,2'-diamino-4,4'-bithiazole}, one nitrate anion and one partially occupied site for a solvent water molecule. The two Cu(II) ions are located in square-planar and square-pyramidal coordination environments, respectively. The separations of the Cu atoms bridged by oxamide and carboxylate groups are 5.2053 (3) and 5.0971 (4) Å, respectively. The complex chains are linked by classical hydrogen bonds to form a layer and then assembled by π-π stacking interactions into a three-dimensional network. The influence of the terminal ligand on the structure of the complex is discussed.