Supramolecular Nature of Multicomponent Crystals Formed from 2,2'-Thiodiacetic Acid with 2,6-Diaminopurine or N9-(2-Hydroxyethyl)adenine.

The synthesis and characterization of the multicomponent crystals formed by 2,2'-thiodiacetic acid (H2tda) and 2,6-diaminopurine (Hdap) or N9-(2-hydroxyethyl)adenine (9heade) are detailed in this report. These crystals exist in a salt rather than a co-crystal form, as confirmed by single crystal X-ray diffractometry, which reflects their ionic nature. This analysis confirmed proton transfer from the 2,2'-thiodiacetic acid to the basic groups of the coformers. The new multicomponent crystals have molecular formulas [(H9heade+)(Htda-)] 1 and [(H2dap+)2(tda2-)]·2H2O 2. These were also characterized using FTIR, 1H and 13C NMR and mass spectroscopies, elemental analysis, and thermogravimetric/differential scanning calorimetry (TG/DSC) analyses. In the crystal packing the ions interact with each other via O-H⋯N, O-H⋯O, N-H⋯O, and N-H⋯N hydrogen bonds, generating cyclic hydrogen-bonded motifs with graph-set notation of R22(16), R22(10), R32(10), R33(10), R22(9), R32(8), and R42(8), to form different supramolecular homo- and hetero-synthons. In addition, in the crystal packing of 2, pairs of diaminopurinium ions display a strong anti-parallel π,π-stacking interaction, characterized by short inter-centroids and interplanar distances (3.39 and 3.24 Å, respectively) and a fairly tight angle (17.5°). These assemblies were further analyzed energetically using DFT calculations, MEP surface analysis, and QTAIM characterization.

H(N3)dap (Hdap = 2,6-Diaminopurine) Recognition by Cu2(EGTA): Structure, Physical Properties, and Density Functional Theory Calculations of [Cu4(µ-EGTA)2(µ-H(N3)dap)2(H2O)2]·7H2O.

Reactions in water between the Cu2(µ-EGTA) chelate (EGTA = ethylene-bis(oxyethyleneimino)tetraacetate(4-) ion) and Hdap in molar ratios 1:1 and 1:2 yield only blue crystals of the ternary compound [Cu4(µ-EGTA)2(µ-H(N3)dap)2(H2O)2]·7H2O (1), which has been studied via single-crystal X-ray diffraction and various physical methods (thermal stability, spectral and magnetic properties), as well as DFT theoretical calculations. In the crystal, uncoordinated water is disordered. The tetranuclear complex molecule also has some irrelevant disorder in an EGTA-ethylene moiety. In the complex molecule, both bridging organic molecules act as binucleating ligands. There are two distorted five- and two six-coordinated Cu(II) centers. Each half of EGTA acts as a tripodal tetradentate Cu(II) chelator, with a mer-NO2 + O(ether, distal) conformation. Hdap exhibits the tautomer H(N3)dap, with the dissociable H-atom on its less basic N-heterocyclic atom. These features favor the efficient cooperation between Cu-N7 or Cu-N9 bonds with appropriate O-EGTA atoms, as N6-H···O or N3-H···O interligand interactions, respectively. The bridging role of both organics determines the tetranuclear dimensionality of the complex. In this crystal, such molecules associate in zig-zag chains built by alternating π-π interactions between the five- or six-atom rings of Hdap ligands of adjacent molecules. DFT theoretical calculations (using two different theoretical models and characterized by the quantum theory of "atoms in molecules") reveal the importance of these π-π interactions between Hdap ligands, as well as those corresponding to the referred hydrogen bonds in the contributed tetranuclear molecule.

The Copper(II)-Thiodiacetate (tda) Chelate as Efficient Receptor of N9-(2-Hydroxyethyl)Adenine (9heade): Synthesis, Molecular and Crystal Structures, Physical Properties and DFT Calculations of [Cu(tda)(9heade)(H2O)]·2H2O.

Considering that Cu(tda) chelate (tda: dithioacetate) is a receptor for adenine and related 6-aminopurines, this study reports on the synthesis, molecular and crystal structures, thermal stability, spectral properties and DFT calculations related to [Cu(tda)(9heade)(H2O)]·2H2O (1) [9heade: N9-(2-hydroxyethyl)adenine]. Concerning the molecular recognition of (metal chelate)-(adenine synthetic nucleoside), 1 represents an unprecedented metal binding pattern (MBP) for 9heade. However, unprecedentedly, the Cu(tda)-9heade molecular recognition in 1 is essentially featured in the Cu-N1(9heade) bond, without any N6-H⋯O(carboxyl tda) interligand interaction. Nevertheless, N1 being the most basic donor for N9-substituted adenines, this Cu-N1 bond is now assisted by an O2-water-mediated interaction (N6-H⋯O2 and O2⋯Cu weak contact). Also, in the crystal packing, the O-H(ol) of 9heade interacts with its own adenine moiety as a result of an O3-water-mediated interaction (O(ol)-H⋯O3 plus O3-H36⋯π(adenine moiety)). Both water-mediated interactions seem to be responsible for serious alterations in the physical properties of crystalline or grounded samples. Density functional theory calculations were used to evaluate the interactions energetically. Moreover, the quantum theory of atoms-in-molecules (QTAIM), in combination with the noncovalent interaction plot (NCIPlot), was used to analyze the interactions and rationalize the existence and relative importance of hydrogen bonding, chalcogen bonding and π-stacking interactions. The novelty of this work resides in the discovery of a novel binding mode for N9-(2-hydroxyethyl)adenine. Moreover, the investigation of the important role of water in the solid state of 1 is also relevant, along with the chalcogen bonding interactions demonstrated by the density functional theory (DFT) study.

Design, Synthesis, and Structure-Activity Relationship Studies of New Quinone Derivatives as Antibacterial Agents.

Resistance to antibacterial agents is a growing global public health problem that reduces the efficacy of available antibacterial agents, leading to increased patient mortality and morbidity. Unfortunately, only 16 antibacterial drugs have been approved by the FDA in the last 10 years, so it is necessary to develop new agents with novel chemical structures and/or mechanisms of action. In response to this, our group takes up the challenge of designing a new family of pyrimidoisoquinolinquinones displaying antimicrobial activities against multidrug-resistant Gram-positive bacteria. Accordingly, the objective of this study was to establish the necessary structural requirements to obtain compounds with high antibacterial activity, along with the parameters controlling antibacterial activity. To achieve this goal, we designed a family of compounds using different strategies for drug design. Forty structural candidates were synthesized and characterized, and antibacterial assays were carried out against high-priority bacterial pathogens. A variety of structural properties were modified, such as hydrophobicity and chain length of functional groups attached to specific carbon positions of the quinone core. All the synthesized compounds inhibited Gram-positive pathogens in concentrations ranging from 0.5 to 64 µg/mL. Two derivatives exhibited minimum inhibitory concentrations of 64 µg/mL against Klebsiella pneumoniae, while compound 28 demonstrated higher potency against MRSA than vancomycin.

Catalytic activation of remote alkenes through silyl-rhodium(III) complexes.

The tandem isomerization-hydrosilylation reaction is a highly valuable process able to transform mixtures of internal olefins into linear silanes. Unsaturated and cationic hydrido-silyl-Rh(III) complexes have proven to be effective catalysts for this reaction. Herein, three silicon-based bidentate ligands, 8-(dimethylsilyl)quinoline (L1), 8-(dimethylsilyl)-2-methylquinoline (L2) and 4-(dimethylsilyl)-9-phenylacridine (L3), have been used to synthesize three neutral [RhCl(H)(L)PPh3] (1-L1, 1-L2 and 1-L3) and three cationic [Rh(H)(L)(PPh3)2][BArF4] (2-L1, 2-L2 and 2-L3) Rh(III) complexes. Among the neutral compounds, 1-L2 could be characterized in the solid state by X-ray diffraction showing a distorted trigonal bipyramidal structure. Neutral complexes (1-L1, 1-L2 and 1-L3) failed to catalyze the hydrosilylation of olefins. On the other hand, the cationic compound 2-L2 was also characterized by X-ray diffraction showing a square pyramidal structure. The unsaturated and cationic Rh(III) complexes 2-L1, 2-L2 and 2-L3 showed significant catalytic activity in the hydrosilylation of remote alkenes, with the most sterically hindered (2-L2) being the most active one.

Rational Coformer Selection in the Development of 6-Propyl-2-thiouracil Pharmaceutical Cocrystals.

Pharmaceutical multicomponent solids have proved to efficiently modulate the physicochemical properties of active pharmaceutical ingredients. In this context, polyphenols are interesting coformers for designing pharmaceutical cocrystals due to their wide safety profile and interesting antioxidant properties. The novel 6-propyl-2-thiouracil multicomponent solids have been obtained by mechanochemical synthesis and fully characterized by powder and single-crystal X-ray diffraction methods. The analysis of supramolecular synthons has been further performed with computational methods, with both results revealing a robust supramolecular organization influenced by the different positions of the hydroxyl groups within the polyphenolic coformers. All novel 6-propyl-2-thiouracil cocrystals show an enhanced solubility profile, but unfortunately, their thermodynamic stability in aqueous media is limited to 24 h.

Enhanced NSAIDs Solubility in Drug-Drug Formulations with Ciprofloxacin.

Drug-drug salts are a kind of pharmaceutical multicomponent solid in which the two co-existing components are active pharmaceutical ingredients (APIs) in their ionized forms. This novel approach has attracted great interest in the pharmaceutical industry since it not only allows concomitant formulations but also has proved potential to improve the pharmacokinetics of the involved APIs. This is especially interesting for those APIs that have relevant dose-dependent secondary effects, such as non-steroidal anti-inflammatory drugs (NSAIDs). In this work, six multidrug salts involving six different NSAIDs and the antibiotic ciprofloxacin are reported. The novel solids were synthesized using mechanochemical methods and comprehensively characterized in the solid state. Moreover, solubility and stability studies, as well as bacterial inhibition assays, were performed. Our results suggest that our drug-drug formulations enhanced the solubility of NSAIDs without affecting the antibiotic efficacy.

Slow Magnetic Relaxation and Modulated Photoluminescent Emission of Coordination Polymer Based on 3-Amino-4-hydroxybenzoate Zn and Co Metal Ions.

As a starting point, a new 3D porous framework with the {[CoL]·0.5DMF·H2O}n chemical formula (where L = 3-amino-4-hydroxybenzoate) is described. Its performance as a single molecule magnet was explored. The study of magnetic properties reveals that Co-MOF shows no frequency-fdependant alternating current (ac) signals under zero direct current (dc) magnetic field, whereas single-molecule magnet behaviour is achieved when CoII ions are diluted in a ZnII based matrix. Interestingly, this strategy renders a bifunctional [CoxZn1-xL]n material that is also characterized by a strong photoluminescent emitting capacity.

Metformin-NSAIDs Molecular Salts: A Path towards Enhanced Oral Bioavailability and Stability.

According to the World Health Organization, more than 422 million people worldwide have diabetes. The most common oral treatment for type 2 diabetes is the drug metformin (MTF), which is usually formulated as a hydrochloride to achieve higher water solubility. However, this drug is also highly hygroscopic, thus showing stability problems. Another kind of worldwide prescribed drug is the non-steroidal anti-inflammatory drug (NSAID). These latter, on the contrary, show a low solubility profile; therefore, they must be administered at high doses, which increases the probability of secondary effects. In this work, novel drug-drug pharmaceutical solids combining MTF-NSAIDs have been synthesized in solution or by mechanochemical methods. The aim of this concomitant treatment is to improve the physicochemical properties of the parent active pharmaceutical ingredients. After a careful solid-state characterization along with solubility and stability studies, it can be concluded that the new molecular salt formulations enhance not only the stability of MTF but also the solubility of NSAIDs, thus giving promising results regarding the development of these novel pharmaceutical multicomponent solids.

Easy Handling and Cost-Efficient Processing of a Tb3+-MOF: The Emissive Capacity of the Membrane-Immobilized Material, Water Vapour Adsorption and Proton Conductivity.

The development of convenient, non-complicated, and cost-efficient processing techniques for packing low-density MOF powders for industry implementation is essential nowadays. To increase MOFs' availability in industrial settings, we propose the synthesis of a novel 3D Tb-MOF (1) and a simple and non-expensive method for its immobilization in the form of pellets and membranes in polymethacrylate (PMMA) and polysulphone (PSF). The photoluminescent properties of the processed materials were investigated. To simulate industrial conditions, stability towards temperature and humidity have been explored in the pelletized material. Water-adsorption studies have been carried out in bulk and processed materials, and because of the considerable capacity to adsorb water, proton-conduction studies have been investigated for 1.

Metal-Organic Frameworks Based on a Janus-Head Biquinoline Ligand as Catalysts in the Transformation of Carbonyl Compounds into Cyanohydrins and Alcohols.

A new family of metal-organic frameworks (MOFs) named GR-MOFs with the chemical formula {[M x (BCA) y ](H2O) z (DMF) w } (x,y,z,w: 1,1,2,0; 1,1.5,0,1; 1,2,2,1; and 1,1,0,2 for GR-MOF-11 to 14, respectively) based on s-block [M: Sr (GR-MOF-11), Ba (GR-MOF-14)] and d-block [M: Y (GR-MOF-12) and Cd (GR-MOF-13)] metals together with the biquinoline ligand 2,2'-bicinchoninic acid (H2BCA) has been synthetized by a solvothermal route and fully characterized by elemental and thermogravimetric analysis, Fourier transform infrared spectroscopy, photoluminescence, particle size distribution through optical microscopy, electrophoretic mobility, and finally, X-ray single-crystal and powder diffraction. The structural characterization reveals that these 2D and 3D MOFs possess a rich variety of coordination modes that maintained the Janus-head topology on the ligand in most of the cases. The new MOFs were studied in the catalyzed cyanosilylation and hydroboration of an extensive group of aldehydes and ketones, wherein the s-block metal-based MOFs GR-MOF-11 and GR-MOF-14 provided the highest efficiency ever reported in the MOF-catalyzed cyanosilylation of carbonyl compounds by using only 0.5 mol % of catalyst loading, room temperature, and solvent-free conditions. Furthermore, the hydroboration of ketones has been reported for the first time with this type of s-block metal catalysts obtaining from moderate to good conversions.

Antibacterial Activity of Two Zn-MOFs Containing a Tricarboxylate Linker.

Metal-organic frameworks (MOFs) can be used as reservoirs of metal ions with relevant antibacterial effects. Here, two novel Zn-based MOFs with the formulas [Zn4(µ4-O)(µ-FA)L2] (GR-MOF-8) and [Zn4(µ4-O)L2(H2O)] (GR-MOF-9) (H3L: 5-((4-carboxyphenyl)ethynyl) in isophthalic acid and FA (formate anion) were solvothermally synthetized and fully characterized. The antibacterial activity of GR-MOF-8 and 9 was investigated against Staphylococcus aureus (SA) and Escherichia Coli (EC) by the agar diffusion method. Both bacteria are among the most relevant human and animal pathogens, causing a wide variety of infections, and are often related with the development of antimicrobial resistances. While both Zn-based materials exhibited antibacterial activity against both strains, GR-MOF-8 showed the highest inhibitory action, likely due to a more progressive Zn release under the tested experimental conditions. This is particularly evidenced in the inhibition of SA, with an increasing effect of GR-MOF-8 with time, which is of great significance to ensure the disappearance of the microorganism.

Lanthanide(III) Ions and 5-Methylisophthalate Ligand Based Coordination Polymers: An Insight into Their Photoluminescence Emission and Chemosensing for Nitroaromatic Molecules.

The work presented herein reports on the synthesis, structural and physico-chemical characterization, luminescence properties and luminescent sensing activity of a family of isostructural coordination polymers (CPs) with the general formula [Ln2(µ4-5Meip)3(DMF)]n (where Ln(III) = Sm (1Sm), Eu (2Eu), Gd (3Gd), Tb (4Tb) and Yb (5Yb) and 5Meip = 5-methylisophthalate, DMF = N,N-dimethylmethanamide). Crystal structures consist of 3D frameworks tailored by the linkage between infinite lanthanide(III)-carboxylate rods by means of the tetradentate 5Meip ligands. Photoluminescence measurements in solid state at variable temperatures reveal the best-in-class properties based on the capacity of the 5Meip ligand to provide efficient energy transfers to the lanthanide(III) ions, which brings intense emissions in both the visible and near-infrared (NIR) regions. On the one hand, compound 5Yb displays characteristic lanthanide-centered bands in the NIR with sizeable intensity even at room temperature. Among the compounds emitting in the visible region, 4Tb presents a high QY of 63%, which may be explained according to computational calculations. At last, taking advantage of the good performance as well as high chemical and optical stability of 4Tb in water and methanol, its sensing capacity to detect 2,4,6-trinitrophenol (TNP) among other nitroaromatic-like explosives has been explored, obtaining high detection capacity (with Ksv around 105 M-1), low limit of detection (in the 10-6-10-7 M) and selectivity among other molecules (especially in methanol).

5-Phenyl-3-(2-phosphono-eth-yl)-1,2,3-triazol-1-ium chloride.

The new triazole-functionalized phospho-nic acid 5-phenyl-3-(2-phosphono-eth-yl)-1,2,3-triazol-1-ium chloride, C10H13N3O3P+·Cl- (PTEPHCl), was synthesized by the 'click' reaction of the alkyl azide diethyl-(2-azido-eth-yl)phospho-nate with phenyl-acetyl-ene to give the dieth-yl[2-(4-phenyl-1H-1,2,3-triazol-1-yl)eth-yl]phospho-nate ester, which was then hydrolyzed under acidic conditions (HCl) to give the 'free' phospho-nic acid. The use of HCl for the hydrolysis caused protonation of the triazole ring, rendering the compound cationic, charged-balanced by a Cl- anion. There are extensive hydrogen-bonding inter-actions in the structure of PTEPHCl, involving the phospho-nic acid (-PO3H2) group, the triazolium ring and the Cl- anion.

catena-Poly[oxidanium [tris{µ-[amino(iminio)methyl]phosphonato}zincate(II)]].

The crystal structure of the anionic zinc-[amino-(iminio)meth-yl]phospho-nate one-dimensional coordination polymer, Zn-AIMP, is reported; the negative charge is balanced by an oxidanium cation (H3O+) to give the composition {(H3O)[Zn(CH4N2PO3)3]} n . The building unit of the coordination polymer comprises a divalent Zn2+ cation (site symmetry ..) and three [amino(iminio)meth-yl]phospho-nate mono-anionic ligands (point group symmetry m). The AIMP ligand exists in a zwitterionic form with a total charge -1 as the phospho-nate is fully deprotonated (-PO3 2-), while the amino-(iminio)methyl moiety is protonated (H2N-C-NH2 +).

Drug-Inclusive Inorganic-Organic Hybrid Systems for the Controlled Release of the Osteoporosis Drug Zoledronate.

Bisphosphonates (BPs) are common pharmaceutical treatments used for calcium- and bone-related disorders, the principal one being osteoporosis. Their antiresorptive action is related to their high affinity for hydroxyapatite, the main inorganic substituent of bone. On the other hand, the phosphonate groups on their backbone make them excellent ligands for metal ions. The combination of these properties finds potential application in the utilization of such systems as controlled drug release systems (CRSs). In this work, the third generation BP drug zoledronate (ZOL) was combined with alkaline earth metal ions (e.g., Sr2+ and Ba2+) in an effort to synthesize new materials. These metal-ZOL compounds can operate as CRSs when exposed to appropriate experimental conditions, such as the low pH of the human stomach, thus releasing the active drug ZOL. CRS networks containing Sr2+ or Ba2 and ZOL were physicochemically and structurally characterized and were evaluated for their ability to release the free ZOL drug during an acid-driven hydrolysis process. Various release and kinetic parameters were determined, such as initial rates and release plateau values. Based on the drug release results of this study, there was an attempt to correlate the ZOL release efficiency with the structural features of these CRSs.

Role of hydrazone substituents in determining the nuclearity and antibacterial activity of Zn(II) complexes with pyrazolone-based hydrazones.

Hydrazones and their metal derivatives are very important compounds in medicinal chemistry due to their reported variety of biological activities, such as antibacterial, antifungal and anticancer action. Five hydrazone-pyrazolone ligands H2Ln (n = 1-5) were prepared and fully characterized and their tautomerism was investigated in the solid state and solution. Five zinc(II) complexes 1-5 of composition [Zn(HLn)2] (n = 1 and 2), [Zn(HLn)2(H2O)2] (n = 3 and 5) and [Zn(HL4)2]n were synthesized and characterized by elemental analysis, IR, 1H, 19F, 13C, and 15N NMR spectroscopy, and ESI mass spectrometry. In addition, the structures of two ligands and three complexes were determined by single-crystal X-ray diffraction. The ligands H2L2 and H2L4 exist both in the NH,NH tautomeric form. Complexes 1 and 2 are mononuclear compounds, while complex 4 is a one-dimensional coordination compound. Density functional theory (DFT) calculations were carried out on proligands, their anions and all zinc complexes, confirming the experimental results, supporting IR and NMR assignments and giving proofs of the mononuclear diaqua structure of complexes 3 and 5. The antibacterial activity of the free ligands and the Zn(II) complexes was established against Escherichia coli and Staphylococcus aureus, and a strong efficiency has been found for Zn(II) complexes, particularly for the polynuclear 4 and the mononuclear diaqua complex 5, the latter containing a ligand with aliphatic and fluorinated substituents able to compromise the permeability of and disrupt the bacterial cell membrane.

Multifunctional Lanthanide-Based Metal-Organic Frameworks Derived from 3-Amino-4-hydroxybenzoate: Single-Molecule Magnet Behavior, Luminescent Properties for Thermometry, and CO2 Adsorptive Capacity.

Herein, we describe and study a new family of isostructural multifunctional metal-organic frameworks (MOFs) with the formula {[Ln5L6(OH)3(DMF)3]·5H2O}n (where (H2L) is 3-amino-4-hydroxybenzoic acid ligand) for magnetism and photoluminescence. Interestingly, three of the materials (Dy-, Er-, and Yb-based MOFs) present single-molecule magnet (SMM) behavior derived from the magnetic anisotropy of the lanthanide ions as a consequence of the adequate electronic distribution of the coordination environment. Additionally, photoluminescence properties of the ligand in combination with Eu and Tb counterparts were studied, including the heterometallic Eu-Tb mixed MOF that shows potential as ratiometric luminescent thermometers. Finally, the porous nature of the framework allowed showing the CO2 sorption capacity.

Combined experimental and theoretical investigation on the magnetic properties derived from the coordination of 6-methyl-2-oxonicotinate to 3d-metal ions.

Five new compounds are reported herein starting from 2-hydroxy-6-methylnicotinic acid (H2h6mnic) and first-row transition metal ions, although H2h6mnic shows a prototropy in solution to lead to the 6-methyl-2-oxonicotinate (6m2onic) ligand that is the molecule eventually present in the compounds. The structural and chemical characterization reveals the following chemical formulae: {[MnNa(µ3-6m2onic)2(µ-6m2onic)(MeOH)]·H2O·MeOH}n (1Mn), {[M2Na2(µ3-6m2onic)2(µ-6m2onic)2(µ-H2O)(H2O)6](NO3)2}n [MII = Co (2Co) and Ni (3Ni)], 2[Cu2(6m2onic)3(µ-6m2onic)(MeOH)]·[Cu2(6m2onic)2(µ-6m2onic)2]·2[Cu(6m2onic)2(MeOH)]·32H2O (4Cu) and {[Cu(µ-6m2onic)2]·6H2O}n (5Cu) (where 6m2onic = 6-methyl-2-oxonicotinate). An unusual structural diversity is observed for the compounds, ranging from isolated complexes (in 4Cu), 1D arrays (in 1Mn and 5Cu) and 3D frameworks (in 2Co and 3Ni). Magnetic properties have been studied for all compounds. Analysis of the magnetic dc susceptibility and magnetization data for 4Cu and 5Cu suggests the occurrence of ferromagnetic exchange, which is well explained by broken-symmetry and CASSCF calculations. The sizeable easy-plane magnetic anisotropy present in compound 2Co allows for a field-induced magnet behaviour with an experimental effective energy barrier of 16.2 cm-1, although the slow relaxation seems to be best described through Raman and direct processes in agreement with the results of ab initio calculations.

Sensing Capacity in Dysprosium Metal-Organic Frameworks Based on 5-Aminoisophthalic Acid Ligand.

Two novel metal-organic frameworks (MOFs), based on dysprosium as the metal and the 5-aminoisophthalic acid (5aip) ligand, have been solvothermally synthesized, with the aim of studying and modulating their luminescence properties according to the variation of solvent in the structure. These materials display intense photo-luminescence properties in the solid state at room temperature. Interestingly, one fascinating sensory capacity of compound 2 regards obtaining a variation of the signal, depending on the solvent to which it is exposed. These results pave the way for a new generation of sensitive chemical sensors.