Piperazine Nitrogen Research Articles

Advanced piperazine-containing inhibitors target microbial β-glucuronidases linked to gut toxicity.

The gut microbiome plays critical roles in human homeostasis, disease progression, and pharmacological efficacy through diverse metabolic pathways. Gut bacterial β-glucuronidase (GUS) enzymes reverse host phase 2 metabolism, in turn releasing active hormones and drugs that can be reabsorbed into systemic circulation to affect homeostasis and promote toxic side effects. The FMN-binding and loop 1 gut microbial GUS proteins have been shown to drive drug and toxin reactivation. Here we report the structure-activity relationships of two selective piperazine-containing bacterial GUS inhibitors. We explore the potency and mechanism of action of novel compounds using purified GUS enzymes and co-crystal structures. Our results establish the importance of the piperazine nitrogen placement and nucleophilicity as well as the presence of a cyclohexyl moiety appended to the aromatic core. Using these insights, we synthesized an improved microbial GUS inhibitor, UNC10206581, that potently inhibits both the FMN-binding and loop 1 GUS enzymes in the human gut microbiome, does not inhibit bovine GUS, and is non-toxic within a relevant dosing range. Kinetic analyses demonstrate that UNC10206581 undergoes a slow-binding and substrate-dependent mechanism of inhibition similar to that of the parent scaffolds. Finally, we show that UNC10206581 displays potent activity within the physiologically relevant systems of microbial cultures and human fecal protein lysates examined by metagenomic and metaproteomic methods. Together, these results highlight the discovery of more effective bacterial GUS inhibitors for the alleviation of microbe-mediated homeostatic dysregulation and drug toxicities and potential therapeutic development.

Drug-drug salts of Naftopidil with non-steroidal anti-inflammatory drugs for potential multi-drug therapy

Drug-drug cocrystals (DDCs) are a subclass of pharmaceutical cocrystals in which both the components of a cocrystal are active drugs. DDCs are the recent advancement based on the crystal engineering approach to overcome the problems associated with conventional combination therapy. They also allow the modulation of the physicochemical properties of parent drugs. Four new drug-drug salts of Naftopidil (NFPD), a BCS class IV anti-cancer drug, were prepared by liquid-assisted grinding and solvent evaporation technique, with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) such as Aspirin (ASP), Tolfenamic acid (TFA), Mefenamic acid (MFA) and Niflumic acid (NIFA) as coformers. The solids obtained were characterized by Single Crystal X-Ray diffraction (SCXRD), Powder X-ray Diffraction (PXRD), Thermo Gravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC). Furthermore, the solubility of NFPD in the solids was determined by the shake flask method. SCXRD analysis showed that O–H···N hydrogen bond interactions found in the pure NFPD crystal structure are replaced by the N+–H···O- and O–H···O hydrogen bond interactions in the drug-drug solids. Additionally, the transfer of a proton from the carboxylic group of NSAIDs to piperazine nitrogen of NFPD is observed in all the drug-drug crystal structures, which suggests the nature of the solids as salts. NFPD-ASP salt exhibited improved solubility (33.2 µg/ml), which is eight-fold higher than the pure NFPD solubility (4.3 µg/ml). NFPD-MFA (0.6 µg/ml), NFPD-TFA (0.17 µg/ml), and NFPD-NIFA (1.35 µg/ml) showed reduced solubility than the pure NFPD. We anticipate that the current research will provide an alternate strategy to overcome the solubility issue of NFPD and provide potential candidates for designing combination therapy to treat complications in Benign Prostatic Hypertrophy (BPH), which involves pain and inflammation.

Versatile applications of a spectrofluorimetric approach based on photo-induced electron transfer blocking of Lurasidone

Photo-induced electron transfer (PET) is one of the most common intermolecular causes that could be responsible for the fluorescence quenching of several fluorophores. Lurasidone is one of these compounds which intrinsic fluorescence could be turned OFF“ in alkaline medium because of the PET effect of the amino group of the piperazine ring. Upon protonation of the piperazine nitrogen atom, its electron lone pair was removed, and hence the fluorescence could be recovered, and the fluorescence is turn ON. Accordingly, a new, simple, environmentally friendly, and selective approach with high sensitivity was developed for quantitation of Lurasidone hydrochloride. The technique relies on measuring the strong native fluorescence of the drug in aqueous solution, which was excited at 316 nm and emitted at 398 nm. Lower detection and quantification limits of 12.9 and 39.0 ng mL−1 were achieved. The fluorescence concentration plot was rectilinear in the range of 30–1600 ng mL−1 with a correlation coefficient of 0.9998. The drug concentrations in commercial tablets and spiked plasma were estimated using the indicated method. The suggested approach was also used to assess how closely commercial tablets complied with USP requirements for content uniformity.

In silico studies of the interaction of the minor groove binder Hoechst 33258 with B-DNA

Interaction of the minor groove binder, Hoechst 33258, with the Dickerson-Drew DNA dodecamer sequence has been investigated using docking, MM/QM, MM/GBSA and molecular dynamics computations to study the modes of binding and the interactions responsible for the binding. Besides the original Hoechst 33258 ligand (HT), a total of 12 ionization and stereochemical states for the ligand are obtained at the physiological pH and have been docked into B-DNA. These states have one or the other or both benzimidazole rings in protonated states, apart from the piperazine nitrogen, which has a quaternary nitrogen in all the states. Most of these states are found to exhibit good docking scores and free energy of binding with B-DNA. The best docked state has been taken further for molecular dynamics simulations and compared with the original HT. This state is protonated at both benzimidazole rings besides the piperazine ring and hence has very highly negative coulombic interaction energy. In both cases, there are strong coulombic interactions, but these are offset by the almost equally unfavorable solvation energies. Thus, the nonpolar forces, particularly van der Waals contacts, dominate the interaction, and the polar interactions highlight subtle changes in the binding energies, leading to more highly protonated states having more negative binding energies. Communicated by Ramaswamy H. Sarma

Halogen Bond Motifs in Cocrystals of N,N,O and N,O,O Acceptors Derived from Diketones and Containing a Morpholine or Piperazine Moiety.

In this study, we investigate the halogen bond acceptor potential of oxygen and nitrogen atoms of morpholine and piperazine fragments when they are peripherally located on N,O,O or N,N,O acceptor molecules. We synthesized four acceptor molecules derived from either acetylacetone or benzoylacetone and cocrystallized them with 1,4-diiodotetrafluorobenzene and 1,3,5-triiodotrifluorobenzene. This resulted in eight cocrystals featuring different topicities and geometric dispositions of donor atoms. In all cocrystals, halogen bonds are formed with either the morpholinyl oxygen atom or the terminal piperazine nitrogen atom. The I···Omorpholine halogen bonds feature lower relative shortening values than I···Nterminal, I···Ocarbonyl, and I···Nproximal halogen bonds. The N and O halogen bond acceptor sites were evaluated through calculations of molecular electrostatic potential values.

Not just a background: pH buffers do interact with lanthanide ions\u2014a Europium(III) case study

The interaction between Eu(III) ion and different pH buffers, popular in biology and biochemistry, viz. HEPES, PIPES, MES, MOPS, and TRIS, has been studied by solution nuclear magnetic resonance spectroscopy (NMR) and time-resolved laser-induced fluorescence spectroscopy (TRLFS) techniques. The Good’s buffers reveal non-negligible interaction with Eu(III) as determined from their complex stability constants, where the sites of interaction are the morpholine and piperazine nitrogen atoms, respectively. In contrast, TRIS buffer shows practically no affinity towards Eu(III). Therefore, when investigating lanthanides, TRIS buffer should be preferred over Good’s buffers.Graphical abstract

Modulating Properties of Piroxicam, Meloxicam and Oxicam Analogues against Macrophage-Associated Chemokines in Colorectal Cancer

The mechanisms underlying the antineoplastic effects of oxicams have not been fully elucidated. We aimed to assess the effect of classic and novel oxicams on the expression/secretion of macrophage-associated chemokines (RTqPCR/Luminex xMAP) in colorectal adenocarcinoma cells, and on the expression of upstream the non-steroidal anti-inflammatory drug (NSAID)-activated genes NAG1, NFKBIA, MYD88, and RELA, as well as at the chemokine profiling in colorectal tumors. Meloxicam downregulated CCL4 9.9-fold, but otherwise the classic oxicams had a negligible/non-significant effect. Novel analogues with a thiazine ring substituted with arylpiperazine and benzoyl moieties significantly modulated chemokine expression to varying degree, upregulated NAG1 and NFKBIA, and downregulated MYD88. They inhibited CCL3 and CCL4, and their effect on CCL2 and CXCL2 depended on the dose and exposure. The propylene linker between thiazine and piperazine nitrogens and one arylpiperazine fluorine substituent characterized the most effective analogue. Only CCL19 and CXCL2 were not upregulated in tumors, nor was CXCL2 in tumor-adjacent tissue compared to normal mucosa. Compared to adjacent tissue, CCL4 and CXCL2 were upregulated, while CCL2, CCL8, and CCL19 were downregulated in tumors. Tumor CCL2 and CCL7 increased along with advancing T and CCL3, and CCL4 along with the N stage. The introduction of arylpiperazine and benzoyl moieties into the oxicam scaffold yields effective modulators of chemokine expression, which act by upregulating NAG1 and interfering with NF-κB signaling.

Cocrystals, Salts, and Salt-Solvates of olanzapine; selection of coformers and improved solubility

Pharmaceutical cocrystals and salts are extensively researched in recent years due to their ability to tune the physicochemical properties of active pharmaceutical ingredients (APIs). A model API, olanzapine, an atypical antipsychotic drug classified as Biopharmaceutical Classification System class II, is used in this study. Cocrystals and salts of olanzapine are discovered using solvent drop grinding and ball milling. Appropriate coformers were selected based on a combination of hydrogen-bond propensity (HBP) and hydrogen-bond coordination (HBC) calculations. Eight new multicomponent phases of olanzapine, including one cocrystal hydrate with phenol; four anhydrous salts with salicylic acid, terephthalic acid, anthranilic acid, 3-hydroxybenzoic acid, and 2-aminoterephthalic acid; one salt dihydrate with terephthalic acid; and one salt solvate with 3-hydroxybenzoic acid and acetonitrile, have been discovered and characterized by PXRD and DSC. One reported cocrystal (olanzapine-resorcinol) has also been considered for the dissolution test. All these newly formed solid phases followed the “ΔpKa rule of 3”. The crystal structures of cocrystal/salts were determined by single-crystal X-ray (sc-XRD) diffraction. With the collected single-crystal data, the crystal packings were found to be primarily stabilized via strong hydrogen bonds between carboxyl, phenolic hydroxyl of co-formers/salt-formers with the piperazine and diazepine nitrogen of olanzapine, which confirmed the predicted result from the HBP and HBC calculations. HPLC coupled with UV–vis detector was used in the solubility and dissolution test instead of UV–vis spectroscopy, to avoid the peak overlap between olanzapine and co-formers/salt-formers. A threefold increase in the solubility was observed in olanzapinium 3-hydroxybenzoate and olanzapinium anthranilate, and an almost fivefold increase in solubility of olanzapinium 2-aminoterephthalate.

L-Arginine/Nitric Oxide Pathway Is Altered in Colorectal Cancer and Can Be Modulated by Novel Derivatives from Oxicam Class of Non-Steroidal Anti-Inflammatory Drugs.

L-arginine/nitric oxide pathway metabolites are altered in colorectal cancer (CRC). We evaluated underlying changes in pathway enzymes in 55 paired tumor/tumor-adjacent samples and 20 normal mucosa using quantitative-PCR and assessed the impact of classic and novel oxicam analogues on enzyme expression and intracellular metabolite concentration (LC-MS/MS) in Caco-2, HCT116, and HT-29 cells. Compared to normal mucosa, ARG1, PRMT1, and PRMT5 were overexpressed in both tumor and tumor-adjacent tissue and DDAH2 solely in tumor-adjacent tissue. Tumor-adjacent tissue had higher expression of ARG1, DDAH1, and DDAH2 and lower NOS2 than patients-matched tumors. The ARG1 expression in tumors increased along with tumor grade and reflected lymph node involvement. Novel oxicam analogues with arylpiperazine moiety at the thiazine ring were more effective in downregulating DDAHs and PRMTs and upregulating ARG2 than piroxicam and meloxicam. An analogue distinguished by propylene linker between thiazine's and piperazine's nitrogen atoms and containing two fluorine substituents was the strongest inhibitor of DDAHs and PRMTs expression, while an analogue containing propylene linker but no fluorine substituents was the strongest inhibitor of ARG2 expression. Metabolic reprogramming in CRC includes overexpression of DDAHs and PRMTs in addition to ARG1 and NOS2 and is not restricted to tumor tissue but can be modulated by novel oxicam analogues.

Solubilization of itraconazole by surfactants and phospholipid-surfactant mixtures: interplay of amphiphile structure, pH and electrostatic interactions

Although surfactants are frequently used in enabling formulations of poorly water-soluble drugs, the link between their structure and drug solubilization capacity is still unclear. We studied the solubilization of the “brick-dust” molecule itraconazole by 16 surfactants and 3 phospholipid:surfactant mixtures. NMR spectroscopy was used to study in more details the drug-surfactant interactions. Very high solubility of itraconazole (up to 3.6 g/L) was measured in anionic surfactant micelles at pH = 3, due to electrostatic attraction between the oppositely charged (at this pH) drug and surfactant molecules. 1H NMR spectroscopy showed that itraconazole is ionized at two sites (2+ charge) at these conditions: in the phenoxy-linked piperazine nitrogen and in the dioxolane-linked triazole ring. The increase of amphiphile hydrophobic chain length had a markedly different effect, depending on the amphiphile type: the solubilization capacity of single-chain surfactants increased, whereas a decrease was observed for double-chained surfactants (phosphatidylglycerols). The excellent correlation between the chain melting temperatures of phosphatidylglycerols and itraconazole solubilization illustrated the importance of hydrophobic chain mobility. This study provides rules for selection of itraconazole solubilizers among classical single-chain surfactants and phospholipids. The basic physics underpinning the described effects suggests that these rules should be transferrable to other “brick-dust” molecules.

Profiling of LINS01 compounds at human dopamine D2 and D3 receptors

Histamine and dopamine neuronal pathways display interesting overlapping in the CNS, especially in the limbic areas, making them very attractive to designing drugs with synergistic and/or additive effects. The roles of these systems to treat schizophrenia, drug addiction, Parkinson’s and Alzheimer’s diseases, among others are widely known. The LINS01 compounds were previously reported as histamine H3 receptor (H3R) antagonists and some of them are under evaluation in rodent memory models. Considering their pharmacological potential and similarities to literature dopamine D2 receptor (D2R) and dopamine D3 receptor (D3R) ligands, this work aimed to evaluate these compounds as ligands these receptors by using [3H]spiperone displacement assays. A set of 11 compounds containing the dihydrobenzofuranyl-piperazine core with substituents at 5-position of dihydrobenzofuran ring and at the piperazine nitrogen was examined. The compounds showed low to moderate affinities at both, D2R and D3R. N-Phenyl compounds LINS01005 (1d), LINS01011 (1h), LINS01012 (1i) and LINS01016 (1k) showed the highest affinities in the set to D3R (Ki 0.3–1.5 µM), indicating that N-phenylpiperazine moiety increases the affinity to this receptor subtype with some selectivity, since they showed lower affinities to D2R (Ki 1.3–5.5 µM). With the LINS01 compounds showing moderate binding affinity, new lead structures for optimization with regards to combined H3R and D2R/D3R-ligands are provided. Histamine and dopamine neuronal pathways display interesting overlapping in the CNS, and thus LINS01 compounds previously reported as histamine H3 receptor antagonists were evaluated as dopamine D2R and D3R ligands. The compounds showed micromolar affinities to both receptors

Tunable ionization degree in cationic polyurethanes and effects on phase separation

A linear non-ionic hard-soft segmented polyurethane (PU0) was prepared by the prepolymer synthesis method. The isocyanate terminated prepolymer, formed by a short and rigid aromatic diisocyanate and a long flexible poly(tetramethylene oxide) (PTMO), was chain extended with a piperazine (PIP) diol derivative. The non-ionic polyurethane was then ionized by a post-modification method, i.e. alkylation of the piperazine nitrogen atoms, thus obtaining cationomers with three different ionization degrees, named PU10, PU50, PU80. The polymers were characterized by means of FT-IR spectroscopy, solution and solid state Nuclear Magnetic Resonance (NMR) spectroscopies, Differential Scanning Calorimetry (DSC) and ThermoGravimetric Analysis (TGA). The chemical structure of the obtained polymers and their cationic content was confirmed by solution state 1H NMR. It was found that the methylation occurs quantitatively up to 50% of the PIP nitrogen atoms and that, even if a large excess of methylating agent is used, in our operating conditions a maximum of 80% of the PIP nitrogen atoms are ionized. All the characterization techniques used suggested that an increasing ionization degree induces a better phase separation between hard and soft domains, with a lower amount of diisocyanate units dispersed in the soft phase. In particular, FT-IR showed that the introduction of ionic sites modifies the hydrogen bond network and induces a better aggregation of the rigid units. In addition, DSC showed that (i) the glass transition temperature values of the polymers decrease and tend to that measured for pure PTMO upon increasing ionization; (ii) a crystalline phase due to PTMO packing in ordered structures appears at the highest ionization degrees, similarly to pure PTMO. 1H Time-Domain NMR and 13C solid state NMR revealed an increase in PTMO mobility with increasing ionic content, in agreement with DSC results.The measurements of proton spin lattice relaxation times in both the laboratory (T1) and rotating (T1ρ) frames allowed limits on the size of the hard domains to be estimated. T1ρ data hint at a phase demixing effect upon increasing the ionization degree.

Discovery of novel 2-(4-aryl-2-methylpiperazin-1-yl)-pyrimidin-4-ones as glycogen synthase kinase-3β inhibitors

We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3β inhibitors from our promising compounds containing a 3-methylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3β inhibitors. SAR studies focused on the nitrogen atom of the piperazine moiety revealed that a phenyl group afforded potent inhibitory activity toward GSK-3β. Docking studies indicated that the phenyl group on the piperazine nitrogen atom and the methyl group on the piperazine make cation-π and CH-π interactions with GSK-3β respectively. 4-Methoxyphenyl analogue 29 showed most potent inhibitory activity toward GSK-3β with good in vitro and in vivo pharmacokinetic profiles, and 29 demonstrated a significant decrease in tau phosphorylation after oral administration in mice.

Structures of the adducts urea:pyrazine (1:1), thiourea:pyrazine (2:1) and thiourea:piperazine (2:1)

Abstract The adducts urea:pyrazine (1:1) (1), thiourea:pyrazine (2:1) (2), and thiourea:piperazine (2:1) (3) were prepared and their structures determined. Adduct 1 forms a layer structure, in which urea chains of graph set C(4)[ R 2 1 ${\rm{R}}_{\rm{2}}^{\rm{1}}$ (6)] run parallel to the b axis and are crosslinked by N–H···N hydrogen bonding to the pyrazine residues. Adduct 2 is a variant of the well-known R 2 2 ${\rm{R}}_{\rm{2}}^{\rm{2}}$ (8) ribbon substructure for urea/thiourea adducts, with the pyrazine molecules attached to the remaining thiourea NH groups via bifurcated hydrogen bonds (N–H···)2S; the more distant end of the pyrazine molecules is crosslinked to another symmetry-equivalent but perpendicular ribbon system, thus creating a three-dimensional packing. The packing of adduct 3 involves thiourea layers parallel to the ab plane; the piperazine molecules occupy the regions between these layers and are linked to the thiourea molecules by two hydrogen bonds (one as donor, one as acceptor) at each piperazine nitrogen atom.

Designing a new cocrystal of olanzapine drug and observation of concomitant polymorphism in a ternary cocrystal system

Olanzapine is an antipsychotic drug which shows donor–acceptor disparity in its polymorphic crystal structures. A strong hydrogen bonding acceptor, piperazine nitrogen, is left unutilized. We reasoned that including hydroquinone as a coformer with two hydroxyl donor groups could overcome the donor–acceptor disparity and facilitate stronger phenol⋯piperazine and phenol⋯diazepine supramolecular synthons between the drug and the coformer. Our co-crystallization attempts were successful in toluene solvent. Two distinct crystal morphologies were observed concomitantly and identified as two polymorphic forms of the drug cocrystal (block, form I, and plate, form II). Unambiguous characterization of cocrystal polymorphs is established through single crystal and powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis and FT-infrared spectroscopy. Both polymorphic forms crystallized in the triclinic space group P with 1 : 1 : 1 drug–coformer–solvent stoichiometry, but they showed significant variations in their unit cell parameters. Structural features that contributed to polymorphism are inferred from the crystal packing and Hirshfeld surface analysis. The subtle structural variations of a closed cavity in form I and a continuous channel in form II for inclusion of toluene are thought to promote concomitant polymorphism. The different onset temperatures for toluene removal in the DSC and TGA scans of polymorphs are linked to the structural environment around toluene in the respective crystal structures and cohesive intermolecular forces. Although cocrystals exhibiting polymorphism have been noticed frequently in recent times, a ternary cocrystal system exhibiting concomitant polymorphism is a rare observation to the best of our knowledge.

Group 12 metal complexes of (2-piperazine-1-yl-ethyl)-pyridin-2-yl-methylene-amine: rare participation of terminal piperazine N in coordination leads to structural diversity.

By using a potential tridentate ligand L ((2-piperazine-1-yl-ethyl)-pyridin-2-yl-methylene-amine), a series of group 12 metal complexes namely, [ZnLHCl2][Zn2LCl5]·2H2O (1), [CdL(SCN)2(CH3OH)]n (2), and [Hg(l-pyCO)Cl2] (3), were synthesized and structurally characterized. In all the complexes the piperazine nitrogen of the ligand takes part in coordination and leads to the complexes of group 12 metal ions having structural diversity. The X-ray diffraction analysis of complex 1 indicates for one Zn(ii) ion a geometry in between trigonal bipyramidal/square pyramidal and for the second a distorted tetrahedral sphere. In the polymeric complex 2 the Cd(ii) ion shows a distorted octahedral environment, while in the mononuclear complex 3, where Hg(ii) exhibits a square-pyramidal geometry, an unexpected condensation between the uncoordinated NH piperazine fragment with 2-pyridinecarboxaldehyde was detected. The M-N bond lengths in all the complexes are in accordance with the metal ionic radius. Continuous shape measures through a DFT approach provide the coordination environment around each metal centre that is comparable with the experimental observations. We have also investigated the importance of hydrogen bonding of methanol in the generation of the polymeric Cd complex 2 along with the rearrangement of the tridentate ligand to generate an octahedral complex. The photoluminescence properties of the complexes as well as of the ligand were investigated in solution at ambient temperature. The low quantum yield of the ligand was ascribed due to a very fast photoinduced electron transfer (PET) from the nitrogen lone pair to the conjugated pyridine moiety. Complexation prevents the electron transfer, and consequently an increase in quantum yield was observed in the complexes. Among the three complexes the highest photoluminescence was exhibited by a Zn complex, being lower in Cd and Hg complexes as a consequence of the heavy atom perturbation effect.

Coordination Chemistry and Structural Dynamics of a Long and Flexible Piperazine-Derived Ligand.

A long and highly flexible internally functionalized dipyridyl ligand α,α'-p-xylylenebis(1-(4-pyridylmethylene)-piper-4-azine), L, has been employed in the synthesis of a series of coordination polymer materials with Co(II), Cd(II), and Ag(I) ions. In poly-[Cd(L)(TPA)] 1 and poly-[Co(L)(IPA)], 2, (TPA = terephthalate, IPA = isophthalate) the ligand adopts a similar linear conformation to that seen in the structure of the unbound molecule and provides a long (2.6 nm) metal-metal bridging distance. Due to the mismatch of edge lengths with that provided by the carboxylate coligands, geometric distortions from the regular dia and (4,4) network geometries for 1 and 2, respectively, are observed. In poly-[Ag2(CF3SO3)2(L)], 3, the ligand coordinates through both pyridine groups and two of the four piperazine nitrogen donors, forming a high-connectivity 2-dimensional network. The compound poly-[Ag2(L)](BF4)2·2MeCN, 4, a porous 3-dimensional cds network, undergoes a fascinating and rapid single-crystal-to-single-crystal rearrangement on exchange of the acetonitrile guests for water in ambient air, forming a nonporous hydrated network poly-[Ag2(L)](BF4)2·2H2O, 5, in which the well-ordered guest water molecules mediate the rearrangement of the tetrafluoroborate anions and the framework itself through hydrogen bonding. The dynamics of the system are examined in greater detail through the preparation of a kinetic product, the dioxane-solvated species poly-[Ag2(L)](BF4)2·2C4H8O2, 6, which undergoes a slow conversion to 5 over the course of approximately 16 h, a transition which can be monitored in real time. The reverse transformation can also be observed on immersing the hydrate 5 in dioxane. The structural features and physical properties of each of the materials can be rationalized based on the flexible and multifunctional nature of the ligand molecule, as well as the coordination behavior of the chosen metal ions.

Synthesis and Characterization of New 3-(4-Arylpiperazin-1-yl)-2-hydroxypropyl 4-Propoxybenzoates and Their Hydrochloride Salts.

Five new 3-(4-arylpiperazin-1-yl)-2-hydroxypropyl 4-propoxybenzoates were designed and synthesized as potential dual antihypertensive agents. The compounds were prepared as free bases and subsequently transformed to hydrochloride salts. The position of protonation of nitrogen atoms in the piperazine ring of hydrochloride salts was determined by means of 13C-CP/MAS and 15N-CP/MAS NMR and IR spectroscopy. Using these solid-state analytical techniques, it was found that both nitrogen atoms were protonated when excess hydrogen chloride was used for preparation of salts. On the other hand, when the equimolar amount of hydrogen chloride was used, piperazine nitrogen substituted by aryl was protonated.

Structure-Based Design of Novel Tetrahydro-Beta-Carboline Derivatives with a Hydrophilic Side Chain as Potential Phosphodiesterase Inhibitors.

Tadalafil is a clinically approved phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction and pulmonary arterial hypertension. It contains two chiral carbons, and the marketed isomer is the 6R, 12aR isomer with a methyl substituent on the terminal nitrogen of the piperazinedione ring. In this report, tadalafil analogues with an extended hydrophilic side chain on the piperazine nitrogen were designed to interact with particular hydrophilic residues in the binding pocket. This leads to analogues with moderate inhibitory activity on phosphodiesterase-5, even for isomers in which chiral carbons are of the S configuration.

Rifampicin adsorbed onto magnetite nanoparticle: SERS study and insight on the molecular arrangement and light effect

In this study, the surface‐enhanced Raman spectroscopy (SERS) technique was used to asses key information regarding the surface adsorption of Rifampicin (RIF) onto magnetite nanoparticle previously dressed with a bilayer of lauric acid (LA). The effects of white light illumination on the physicochemical properties of the RIF molecule were also investigated. Transmission electron microscopy, dynamic light scattering, zeta‐potential, and Fourier transform infrared spectroscopy were also employed to characterize the investigated materials. Vibrational mode assignments for the SERS spectra and comparison between the data recorded from the free and adsorbed RIF provided insights for the adsorption of this biomolecule onto the LA‐bilayer dressed magnetite nanoparticle. The results suggested that the species binding to the outer carboxylate group of the LA‐bilayer is more likely the piperazine nitrogen adjacent to the imine nitrogen. The SERS data also revealed the enhancement of the RIF molecule stability to white light irradiation while adsorbed onto the magnetite nanoparticle. Copyright © 2015 John Wiley & Sons, Ltd.