Sequential homo-coupling Diels-Alder/retro Diels-Alder reaction of 5,5′-bi-1,2,4-triazine-containing thiamacrocycles as a new route to thiacrown ethers incorporating a 2,2′-bipyridine subunit

A new route to thiacrown ethers 5a-d and 6a-d incorporating a 2,2′-bipyridine subunit is elaborated using, (1) homo-coupling of 1,2,4-triazine sulfides 3a-d tethered to poly(ethylene glycol) chains with potassium cyanide and (2) Diels-Alder/retro Diels-Alder reaction with norbornadiene or 1-pyrrolidino-1-cyclopentene as the key steps.     

Optimized derivatization of acidic herbicides with trimethylsilyldiazomethane for GC analysis

In the present study, the preparation of methyl esters of chlorophenoxy acids with trimethylsilyldiazomethane (TMSD) is reported. TMSD is a mild and safe alternative to the highly toxic, thermally labile, and explosive diazomethane. Due to the novelty of this method, the characteristics of the reaction were investigated and the derivatization procedure was screened for statistically significant factors. The parameters identified as influential are the amount of methanol as well as reaction time and temperature. A careful optimization by a complete factorial response surface design was carried out to generate optimal reaction conditions with respect to maximum recovery and reaction yield. Special emphasis has been given to an accurate validation of the derivatization procedure. LODs were determined between 4.1 and 8.1 ng/mL for the enriched sample and linearity was proofed for more than five orders of magnitude. The applicability of the method was demonstrated by the analyses of quality control material including sample preparation with SPE. Polar herbicides investigated in the study belong to acetic acid (2,4-D, MCPA, and 2,4,5-T), butanoic acid (MCPB), and propanoic acid (mecoprop). An efficient, fast, and high-throughput method for the determination of polar herbicides including the potential for automation is proposed.     

Gold nanoparticle-enhanced target for MS analysis and imaging of harmful compounds in plant,animal tissue and on fingerprint

Gold nanoparticle-enhanced target (AuNPET) was used for detailed investigation of various materials of biological origin – human fingerprint, onion bulb and chicken liver. Analysis of these objects was focused on toxic and harmful compounds – designer drug containing pentedrone, diphenylamine in onion and potentially cancerogenic metronidazole antibiotic in liver. Detection of large quantity of endogenous compounds from mentioned objects is also shown. Most of analyzed compounds were also localized with MS imaging and relationship between their function and location was discussed. Detected compounds belong to a very wide range of chemical compounds such as saccharides, ionic and non-ionic glycerides, amino acids, fatty acids, sulfides, sulfoxides, phenols etc. Fingerprint experiments demonstrate application of AuNPET for detection, structure confirmation and also co-localization of drug with ridge patterns proving person-drug contact.     

Ring-Opening Polymerization of Lactones Initiated with Metal Hydroxide-Activated Macrocyclic Ligands: Determination of Mechanism and Structure of Polymers

Anhydrous alkali metal hydroxide (KOH, NaOH, and LiOH)-activated macrocyclic ligand complexing metal cations, i.e., coronands 12C4, 15C5, 18C6, DCH24C8, and cryptand C222, were selected for initiation of β-butyrolactone (β-BL) and ε-caprolactone (ε-CL) polymerization. It was found that β-BL polymerizes in the presence of KOH/18C6, KOH/C222, and NaOH/C222 systems. The real initiators in this case are two salts, potassium 3-hydroxybutyrate and potassium trans-crotonate, which are responsible for the formation of two fractions of the obtained polymer. ε-CL underwent polymerization with KOH or NaOH activated by all ligands used or without the ligand but with LiOH/12C4. Using KOH-activated strong ligands, i.e., 15C5, 18C6, or C222, two polymer fractions were generated containing linear and, unexpectedly, also cyclic macromolecules. The mechanism of the studied processes is discussed.     

Cocrystals “Divorce and Marriage”: When a Binary System Meets an Active Multifunctional Synthon in a Ball Mill

A well-defined and stable “AB” binary system in the presence of “C” a crystalline synthon ground in a ball mill undergoes selective transformation in the solid state according to the equation AB+C→AC+B. When the amount of C is increased two times then the equation AB+2C→AC+BC is valid. The other variants are more complex. The pathway BC+A is allowed and leads to the AC and B products. The pathway AC+B is not preferred, and no transformation is observed. These non-obvious correlations were observed for cocrystal of barbituric acid (BA):thiobarbituric acid (TBA) recently reported by Shemchuk et al. (Chem. Commun. 2016 , 52, 11815–11818) in the presence of 1-hydroxy-4,5-dimethyl-imidazole 3-oxide (HIMO). This synthon shows high affinity for the BA_0.5TBA_0.5 cocrystal as well for its individual components, BA and TBA. Single-quantum, double-quantum (SQ-DQ) 2D ¹H very fast MAS NMR with a spinning rate of 60 kHz was employed as a basic and most diagnostic tool for the study of cocrystals transformations. Analysis of the experimental data was supported by theoretical calculations, including computation of the stabilization energy, E^stab, defined as the energy difference between the energy of a co-crystal and the sum of the energies of particular components in the respective stoichiometric ratios. Two mechanisms of synthon replacement have been proposed. Pathway 1 assumes a concerted mechanism of substitution. In this approach, synthon attack is synchronized in time with the departure of one of the components of the binary system. Pathway 2 implies a non-concerted process, with an intermediate stage in which three separate components are present. Evidence suggesting a preference for Pathway 2 is shown.     

2,2′-Dithiobispyrazine: about the disulfide bond

X-ray diffraction studies reveal that pyrazine-2-thiol undergoes condensation to 2,2′-dithiobispyrazine [systematic name: 2-(pyrazin-2-yldisulfanyl)pyrazine], C₈H₆N₄S₂ ( I ), under aerial conditions. In the molecule of I , the pyrazine rings are arranged in an almost perpendicular manner, with an absolute value of the C—S—S—C torsion angle of −91.45 (6)°. A search in the Cambridge Structural Database confirmed that such a conformation is typical for disulfide compounds. Three different rotamers of disulfide I were studied using quantum theoretical studies. The rotamer of lowest energy was observed in the crystalline state in the structure stabilized by hydrogen-bond, chalcogen-bond and stacking interactions. Further quantum chemical computations confirm that 2,2′-dithiobispyrazine can react according to the S_N2 mechanism.     

Biphenylalkoxyamine Derivatives–Histamine H3 Receptor Ligands with Butyrylcholinesterase Inhibitory Activity

Neurodegenerative diseases, e.g., Alzheimer’s disease (AD), are a key health problem in the aging population. The lack of effective therapy and diagnostics does not help to improve this situation. It is thought that ligands influencing multiple but interconnected targets can contribute to a desired pharmacological effect in these complex illnesses. Histamine H₃ receptors (H₃Rs) play an important role in the brain, influencing the release of important neurotransmitters, such as acetylcholine. Compounds blocking their activity can increase the level of these neurotransmitters. Cholinesterases (acetyl- and butyrylcholinesterase) are responsible for the hydrolysis of acetylcholine and inactivation of the neurotransmitter. Increased activity of these enzymes, especially butyrylcholinesterase (BuChE), is observed in neurodegenerative diseases. Currently, cholinesterase inhibitors: donepezil, rivastigmine and galantamine are used in the symptomatic treatment of AD. Thus, compounds simultaneously blocking H₃R and inhibiting cholinesterases could be a promising treatment for AD. Herein, we describe the BuChE inhibitory activity of H₃R ligands. Most of these compounds show high affinity for human H₃R (K_i < 150 nM) and submicromolar inhibition of BuChE (IC₅₀ < 1 µM). Among all the tested compounds, 19 (E153, 1-(5-([1,1′-biphenyl]-4-yloxy)pentyl)azepane) exhibited the most promising in vitro affinity for human H₃R, with a K_i value of 33.9 nM, and for equine serum BuChE, with an IC₅₀ of 590 nM. Moreover, 19 (E153) showed inhibitory activity towards human MAO B with an IC₅₀ of 243 nM. Furthermore, in vivo studies using the Passive Avoidance Task showed that compound 19 (E153) effectively alleviated memory deficits caused by scopolamine. Taken together, these findings suggest that compound 19 can be a lead structure for developing new anti-AD agents.     

Influence of Fluorine Substitution on Nonbonding Interactions in Selected Para-Halogeno Anilines

A series of 4-halogeno aniline derivatives was studied employing combined theoretical and experimental methods (i. e. crystal structure analysis and vibrational spectroscopies). This simplified model system was selected to shed light on the impact of fluorine substitution on the formation of noncovalent interactions such as halogen bonds (XBs) and hydrogen bonds (HBs), which are key interactions in fluorinated/halogenated drug-protein complex formation. Comparative analysis of three previously reported and five newly determined crystal structures indicated that, in most cases, 2-fluoro and 2,6-difluoro substitution of 4-X anilines increases the ability of adjacent amine to form strong N−H⋅⋅⋅N HBs. Additionally, fluorine substituents in the difluorinated derivatives are competitive and attractive HB and XB acceptors and increase the probability of halogen-halogen contacts. A peculiar observation was made for 4-iodoaniline and 2,6-difluoro-4-iodoaniline, which form distinct interaction patterns compared to the corresponding 4-Cl and 4-Br analogs. The observed intramolecular N−H⋅⋅⋅F interactions lead to additional NH bands in the FT-IR spectra.     

The Annealing of Acetylated Potato Starch with Various Substitution Degrees

This study aimed to determine the effect of “annealing” acetylated potato starch with a homogenous granule size and various degrees of substitution on the thermal pasting characteristics (DSC), resistance to amylases, rheology of the prepared pastes, swelling power and dynamics of drug release. A fraction of large granules was separated from native starch with the sedimentation method and acetylated with various doses of acetic anhydride (6.5, 13.0 or 26.0 26 cm³/100 g starch). The starch acetates were then annealed at slightly lower temperatures than their pasting temperatures. The annealing process caused an almost twofold increase in the resistance to amylolysis and a threefold increase in the swelling power of the modified starch preparations. The heat of phase transition decreased almost two times and the range of starch pasting temperatures over two times, but the pasting temperature itself increased by ca. 10 °C. The 40 g/100 g addition of the modified starch preparation decreased the rate of drug release from a hydrogel by ca. one-fourth compared to the control sample.     

Ipertrofan Revisited—The Proposal of the Complete Stereochemistry of Mepartricin A and B

Being a methyl ester of partricin, the mepartricin complex is the active substance of a drug called Ipertrofan (Tricandil), which was proven to be useful in treatment of benign prostatic hyperplasia and chronic nonbacterial prostatitis/chronic pelvic pain syndrome. Nevertheless, no direct structural evidence on the stereochemistry of its components has been presented to date. In this contribution, we have conducted detailed, NMR-driven stereochemical studies on mepartricins A and B, aided by molecular dynamics simulations. The absolute configuration of all the stereogenic centers of mepartricin A and B was defined as 3R, 7R, 9R, 11S, 13S, 15R, 17S, 18R, 19S, 21R, 36S, 37R, and 38S, and proposed as 41R. The geometry of the heptaenic chromophore of both compounds has been established as 22E, 24E, 26E, 28Z, 30Z, 32E, and 34E. Our studies on mepartricin ultimately proved that partricins A and B are structurally identical to the previously described main components of the aureofacin complex: gedamycin and vacidin, respectively. The knowledge of the stereochemistry of this drug is a fundamental matter not only in terms of studies on its molecular mode of action, but also for potential derivatization, aiming at improvement of its pharmacological properties.