Study of the growth of <Emphasis Type="Italic">Enterococcus faecalis</Emphasis>, <Emphasis Type="Italic">Escherichia coli</Emphasis> and their mixtures by microcalorimetry

In a majority of environments, microbes live as interacting communities. Microbial communities are composed of a mix of microbes with often unknown functions. Polymicrobial diseases represent the clinical and pathological manifestations induced by the presence of multiple infectious agents. These diseases are difficult to diagnose and treat and usually are more severe than monomicrobial infections. The interaction relationship between Enterococcus faecalis and Escherichia coli was researched using a Calvet calorimeter. Three mixtures of both bacteria were prepared in the following proportions: 20 + 80 % (0.2 mL E. faecalis + 0.8 mL E. coli), 50 + 50 % (0.5 mL E. faecalis + 0.5 mL E. coli) and 80 + 20 % (0.8 mL E. faecalis + 0.2 mL E. coli). Experiments were carried out at concentration of 10⁶ CFU mL^?1 and a constant temperature of 309.65 K. The differences in shape of graph of E. faecalis, E. coli and their mixtures were compared. Also, the thermokinetic parameters such as detection time (t _d), growth constant (k), generation time (G) and the amount of heat released (Q) were calculated.     

<Emphasis Type="Italic">cis</Emphasis>-Dioxomolybdenum(VI) complexes of sterically encumbered phenol-based tetradentate N<Subscript>2</Subscript>O<Subscript>2</Subscript> ligands: Structural,spectroscopic, and electrochemical studies

Two cis-dioxomolybdenum(VI) complexes [MoO₂L] (L: L ¹, 2 and L: L ², 3) in a phenol-based sterically encumbered N₂O₂ ligand environment have been synthesized, and their crystallographic characterizations are reported. The orange crystals of 2 are monoclinic, space group P2₁/a with unit cell dimensions as a=16.2407(17) Å, b=7.2857(8) Å, c=18.400(2) Å, β=98.002(9)°, Z=4, and d _cal=1.486 g cm^?3. The light orange crystals of 3, however, are orthorhombic, space group, Pbcn, with unit cell dimensions a=8.3110(12) Å, b=12.637(3) Å, c=34.673(5) Å, Z=4, and d _cal=1.187 g cm^?3. The structures were refined by a full-matrix least-squares procedure on F ² to a final R=0.046 (0.055 for 3) using 4944 (3677) all independent data. In both the cases, the Mo atom exists in a distorted octahedral geometry defined by a N₂O₄ donor set, which features a cis-Mo(–O)₂ and a trans-Mo(OPh)₂ arrangement. Compound 2 undergoes a quasireversible one-electron reduction at ?1.3 V vs Ag/AgCl reference due to Mo^VIO₂/Mo^VO₂ electron transfer and thus providing a rare example of steric solution to the comproportionation–dimerization problem encountered frequently in the development of valid biomimetic models for the active sites of oxomolybdenum enzymes.     

A comparison of energy changes accompanying growth processes by <Emphasis Type="Italic">Saccharomyces cerevisiae</Emphasis>

Calculations are made using the equations Δ_r G = Δ_r H ? TΔ_r S and Δ_r X = Δ_r H ? Δ_r Q where Δ_r X represents the free energy change when the exchange of absorbed thermal energy with the environment is represented by Δ_r Q. The symbol Q has traditionally represented absorbed heat. However, here it is used specifically to represent the enthalpy listed in tabulations of thermodynamic properties as (H _T  ? H ₀) at T = 298.15 K, the reason being that for a given substance TS equals 2.0 Q for solid substances, with the difference being greater for liquids, and especially gases. Since Δ_r H can be measured, and is tangibly the same no matter what thermodynamics are used to describe a reaction equation, a change in the absorbed heat of a biochemical growth process system as represented by either Δ_r Q or TΔ_r S would be expected to result in a different calculated value for the free energy change. Calculations of changes in thermodynamic properties are made which accompany anabolism; the formation of anabolic, organic by-products; catabolism; metabolism; and their respective non-conservative reactions; for the growth of Saccharomyces cerevisiae using four growth process systems. The result is that there is only about a 1% difference in the average quantity of free energy conserved during growth using either Eq. 1 or 2. This is because although values of TΔ_r S and Δ_r Q can be markedly different when compared to one another, these differences are small when compared to the value for Δ_r G or Δ_r X.     

Structure,bioactivity and theoretical study of 1-cyano-<Emphasis Type="Italic">N</Emphasis>-p-tolylcyclo-propanecarboxamide

A novel cyclopropane derivative, 1-cyano-N-p-tolylcyclopropanecarboxamide (C₁₂H₁₂N₂O, Mr = 200.24) was synthesized and its structure was studied by X-ray diffraction, FTIR, ¹H and ¹³C NMR spectrum and MS. The crystals are monoclinic, space group P2_1/c with a = 7.109 (4), b = 13.758 (7), c = 11.505 (6) Å, α = 90.00, β = 102.731 (8), γ = 90.00 °, V = 1097.6 (9) ų, Z = 4, F(000) = 312, D _c  = 1.212 g/cm³, μ = 0.0800 mm^?1, the final R = 0.0490 and wR = 0.1480 for 1,375 observed reflections with I > 2σ(I). A total of 6,109 reflections were collected, of which 2,290 were independent (R _int = 0.0290). Theoretical calculation of the title compound was carried out with HF/6-31G (d,p), B3LYP/6-31G (d,p), MP2/6-31G (d,p). The full geometry optimization was carried out using 6-31G(d,p) basis set, and the frontier orbital energy. Atomic net charges were discussed, and the structure-activity relationship was also studied. The preliminary biological test showed that the synthesized compound is bioactive against the KARI of Escherichia coli.     

Simultaneous Production of Amyloglucosidase and Exo-Polygalacturonase by <Emphasis Type="Italic">Aspergillus niger</Emphasis> in a Rotating Drum Reactor

Simultaneous production of amyloglucosidase (AMG) and exo-polygalacturonase (exo-PG) was carried out by Aspergillus niger in substrate of defatted rice bran in a rotating drum bioreactor (RDB) and studied by a 3¹ × 2² factorial experimental design. Variables under study were A. niger strains (A. niger NRRL 3122 and A. niger t0005/007-2), types of inoculum (spore suspension and fermented bran), and types of inducer (starch, pectin, and a mix of both). Solid-state fermentation process (SSF) was conducted at 30 °C under 60-vvm aeration for 96 h in a pilot scale. Production of AMG and exo-PG was significantly affected by the fungal strain and the type of inoculum, but inducers did not trigger any significant effect, an evidence of the fact that these enzymes are constitutive. The maximum activity of exo-PG was 84 U g_dm ^?1 whereas the maximum yield of AMG was 886.25 U g_dm ^?1.     

Heterologous Expression and Characterization of an Acidic GH11 Family Xylanase from <Emphasis Type="Italic">Hypocrea orientalis</Emphasis>

A gene encoding glycoside hydrolase family 11 xylanase (HoXyn11B) from Hypocrea orientalis EU7–22 was expressed in Pichia pastoris with a high activity (413 IU/ml). HoXyn11B was partly N-glycosylated and appeared two protein bands (19–29 kDa) on SDS-PAGE. The recombinant enzyme exhibited optimal activity at pH 4.5 and 55 °C, and retained more than 90% of the original activity after incubation at 50 °C for 60 min. The determined apparent K _m and V _max values using beechwood xylan were 10.43 mg/ml and 3246.75 IU/mg, respectively. The modes of action of recombinant HoXyn11B on xylo-oligosaccharides (XOSs) and beechwood xylan were investigated by thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), which indicated that the modes of action of HoXyn11B are different from HoXyn11A since it is able to release a significant amount of xylose from various substrates. This study provides an opportunity to better understand the hydrolysis mechanisms of xylan by xylanases from Trichoderma.     

Catalytic Properties of Two <Emphasis Type="Italic">Rhizopus oryzae</Emphasis> 99-880 Glucoamylase Enzymes Without Starch Binding Domains Expressed in <Emphasis Type="Italic">Pichia pastoris</Emphasis>

Catalytic properties of two glucoamylases, AmyC and AmyD, without starch binding domains from Rhizopus oryzae strain 99-880 are determined using heterologously expressed enzyme purified to homogeneity. AmyC and AmyD demonstrate pH optima of 5.5 and 6.0, respectively, nearly one unit higher than the Rhizopus AmyA glucoamylase enzyme. Optimal initial activities are at 60 and 50 °C for AmyC and AmyD, respectively. Inactivation of both enzymes occurs at 50 °C following 30 min pre-incubation. The two enzymes demonstrate substantially slower catalytic rates toward soluble starch relative to AmyA. AmyC has similar k _cat and K _m for oligosaccharides to other Rhizopus and Aspergillus glucoamylases; however, the enzyme has a 2-fold lower K _m ^maltose . AmyD has a 3-fold higher K _m and lower k _cat for maltooligosaccharides than AmyC and other glucoamylases. AmyC (but not AmyD) exhibits substrate inhibition. K _i for substrate inhibition decreases with increasing length of the oligosaccharides. Data from pre-steady-state binding of AmyC to maltose and maltotriose and pre-steady-state to steady-state catalytic turnover experiments of AmyC acting on maltotriose were used to interrogate models of substrate inhibition. In the preferred model, AmyC accumulates an enzyme-maltose-maltotriose dead-end complex in the steady state.     

Molecular and crystal structure of 15-acetylsongorine and songoramine isolated from <Emphasis Type="Italic">Aconitum szechenyianum</Emphasis> Gay

Two napelline skeletal diterpenoid alkaloids 15-acetylsongorine, C₂₄H₃₃NO₄ I, and songoramine, C₂₂H₂₉NO₃ II, were first isolated from the roots of Aconitum Szechenyianum Gay. The crystal structures were determined by X-ray single-crystal diffraction analysis. The crystal I is the triclinic system with space group P1 having unit cell parameters of a = 9.360(8) Å, b = 11.593(9) Å, c = 11.830(16) Å, α = 113.223(15)°, β = 105.950(16)°, γ = 101.296(12)°, and Z = 2. Hydrogen bonds O–H···O and O–H···N joint the molecules into dimer. The crystal II belongs to the orthorhombic system with space group P2₁2₁2₁ having unit cell parameters of a = 8.950(2) Å, b = 13.272(3) Å, c = 15.454(4) Å and Z = 4. The O–H···O hydrogen bonding interaction links the molecule into linear chains. The distortion of rings of compound I and II were evaluated by calculation of the Cremer and Pople puckering parameters. The presence of the C–O–C bond in the compound II results in the changes of ring conformations compared with that of the compound I.     

Synthesis and characterization of a new monophosphate (C<Subscript>6</Subscript>H<Subscript>16</Subscript>N<Subscript>2</Subscript>)(H<Subscript>2</Subscript>PO<Subscript>4</Subscript>)<Subscript>2</Subscript>

Chemical preparation, crystal structure, and NMR spectroscopy of a new trans-2,5-dimethylpiperazinium monophosphate are given. This new compound crystallizes in the triclinic system, with the space group P-1 and the following parameters: a = 6.5033(3), b = 7.6942(4), c = 8.1473(5) Å, α = 114.997(3), β = 92.341(3), γ = 113.136(3), V = 329.14(3) ų, Z = 1, and D_x = 1.565 g cm^?3. The crystal structure has been determined and refined to R = 0.030 and R _w(F ²) = 0.032 using 1558 independent reflections. The structure can be described as infinite [H₂PO₄] _n ^n? chains with (C₆H₁₆N₂)²⁺ organic cations anchored between adjacent polyanions to form columns of anions and cations running along the b axis. This compound has also been investigated by IR, thermal, and solid-state, ¹³C and ³¹P MAS NMR spectroscopies and Ab initio calculations.     

Synthesis,crystal structure,and thermodynamics of a high-nitrogen copper complex with <Emphasis Type="Italic">N</Emphasis>, <Emphasis Type="Italic">N</Emphasis>-bis-(1(2)H-tetrazol-5-yl) amine

A new high-nitrogen complex [Cu(Hbta)₂]·4H₂O (H₂bta = N,N-bis-(1(2)H-tetrazol-5-yl) amine) was synthesized and characterized by elemental analysis, single crystal X-ray diffraction and thermogravimetric analyses. X-ray structural analyses revealed that the crystal was monoclinic, space group P2(1)/c with lattice parameters a = 14.695(3) Å, b = 6.975(2) Å, c = 18.807(3) Å, β = 126.603(1)°, Z = 4, D _c = 1.888 g cm^?3, and F(000) = 892. The complex exhibits a 3D supermolecular structure which is built up from 1D zigzag chains. The enthalpy change of the reaction of formation for the complex was determined by an RD496–III microcalorimeter at 25 °C with the value of ?47.905 ± 0.021 kJ mol^?1. In addition, the thermodynamics of the reaction of formation of the complex was investigated and the fundamental parameters k, E, n, \( \Updelta S_{ \ne }^{{{\uptheta}}} \), \( \Updelta H_{ \ne }^{{{\uptheta}}} \), and \( \Updelta G_{ \ne }^{{{\uptheta}}} \) were obtained. The effects of the complex on the thermal decomposition behaviors of the main component of solid propellant (HMX and RDX) indicated that the complex possessed good performance for HMX and RDX.     

A Novel 2-Keto-<Emphasis Type="SmallCaps">d</Emphasis>-Gluconic Acid High-Producing Strain <Emphasis Type="Italic">Arthrobacter globiformis</Emphasis> JUIM02

2-Keto-d-gluconic acid (2KGA) is mainly used for industrial production of erythorbic acid, a food antioxidant. In this study, a 2KGA producing strain JUIM02 was firstly identified as Arthrobacter globiformis by morphological observation and 16S rDNA sequencing. The 2KGA synthetic capacity of A. globiformis JUIM02 was evaluated by both fermentation and bioconversion, with 180 g/L dextrose monohydrate as substrates, in shake flasks and 5 L fermenters. For fermentation, 2KGA titer, yield, molar yield, and productivity of JUIM02 reached 159.05 g/L, 0.97 g/g, 90.18%, and 6.63 g/L/h in 24 h. For non-sterile and buffer-free bioconversion by free resting cells (~?3.2 g/L dry cell weight) of JUIM02, these data were 172.96 g/L, 1.06 g/g, 98.07%, and 5.41 g/L/h in 32 h. Moreover, JUIM02 resting cells could be repeatedly used. Resting cells stored at 4 °C within 30 days showed stable bioconversion capacity, with 2KGA titers ≥?171.50 g/L, yields ≥?1.04 g/g, and molar yields ≥?97.24%. The 2KGA synthetic pathway in A. globiformis, which was rarely reported, was also speculated similar to Pseudomonas and verified preliminarily. In conclusion, A. globiformis JUIM02 is a promising 2KGA industrial-producing strain suitable for various production methods and a suitable object for 2KGA metabolism research of A. globiformis.     

Synthesis,antifungal and insecticidal activity of novel [1,2,4]triazolo[4,3-<Emphasis Type="Italic">a</Emphasis>]pyridine derivatives containing a sulfide substructure

A series of [1,2,4]triazolo[4,3-a]pyridine derivatives bearing a sulfide substructure was designed, synthesized and characterized via ¹H·NMR, ¹³C·NMR, IR and elemental analyses. Bioassay Results indicated some of the derivatives displayed good fungicidal activity on Rhizoctonia cerealis, moderated insecticidal activity against Plutella xylostella and good insecticidal activity on Helicoverpa armigera. The inhibitory effects of compounds 4g and 4u against Rhizotonia cerealis were 70.9% at 50 μg mL^?1; the IC₅₀ values of compounds 4d and 4s against Plutella xylostella were 43.87 and 50.75 μg mL^?1, respectively. And the IC₅₀ values of compounds 4d, 4q, and 4s on Helicoverpa armigera were 58.3, 77.14 and 65.31 μg mL^?1, respectively, which were better than that of commercial chlorpyrifos (103.77 μg mL^?1).     

Saw-sedge <Emphasis Type="Italic">Cladium mariscus</Emphasis> as a functional low-cost adsorbent for effective removal of 2,4-dichlorophenoxyacetic acid from aqueous systems

For the first time in the published literature, a study is described concerning the use of the saw-sedge Cladium mariscus (C. mariscus) for adsorption of 2,4-dichlorophenoxyacetic acid (2,4-D) from aqueous systems. Among the experiments carried out, the elemental composition of C. mariscus was determined (C = 48.0 %, H = 7.1 %, N = 0.95 %, S = 0.4 %), FTIR spectroscopic analysis was performed to confirm the chemical structure of the adsorbent, and porous structure parameters were measured: BET surface area (A _BET  = 0.6 m²/g), total pore volume (V _p  = 0.001 cm³/g) and average pore size (S _p  = 6.6 nm). It was shown that the effectiveness of removal of 2,4-D from aqueous systems using C. mariscus depends on parameters of the process: contact time, system pH, mass of sorbent, and temperature. Maximum adsorption was attained for a solution at pH = 3. Further increase in the alkalinity of the tested systems led to a reduction in the effectiveness of the process. The kinetic of adsorption of 2,4-D by C. mariscus was also determined, and thermodynamic aspects were investigated. The experimental data obtained correspond to a pseudo-second-order kinetic model of type 1. Additionally the negative values obtained for ΔHº indicate that the process is exothermic, and the negative values of ΔGº show it to be spontaneous. As the temperature of the system increases the spontaneity of adsorption is reduced, in accordance with the exothermic nature of the process.     

Bioethanol Production from Soybean Residue via Separate Hydrolysis and Fermentation

Bioethanol was produced using polysaccharide from soybean residue as biomass by separate hydrolysis and fermentation (SHF). This study focused on pretreatment, enzyme saccharification, and fermentation. Pretreatment to obtain monosaccharide was carried out with 20% (w/v) soybean residue slurry and 270 mmol/L H₂SO₄ at 121 °C for 60 min. More monosaccharide was obtained from enzymatic hydrolysis with a 16 U/mL mixture of commercial enzymes C-Tec 2 and Viscozyme L at 45 °C for 48 h. Ethanol fermentation with 20% (w/v) soybean residue hydrolysate was performed using wild-type and Saccharomyces cerevisiae KCCM 1129 adapted to high concentrations of galactose, using a flask and 5-L fermenter. When the wild type of S. cerevisiae was used, an ethanol production of 20.8 g/L with an ethanol yield of 0.31 g/g consumed glucose was obtained. Ethanol productions of 33.9 and 31.6 g/L with ethanol yield of 0.49 g/g consumed glucose and 0.47 g/g consumed glucose were obtained in a flask and a 5-L fermenter, respectively, using S. cerevisiae adapted to a high concentration of galactose. Therefore, adapted S. cerevisiae to galactose could enhance the overall ethanol fermentation yields compared to the wild-type one.     

Tetrakis [<Emphasis Type="Italic">N</Emphasis>-(2-pyridyl) sulfonamide] di palladium: synthesize,X-ray diffraction,antibacterial properties and as a novel binuclear Pd-complex for coupling reactions

The N-(2-pyridyl) 4-toluene sulfonamide as a free ligand (PTS) was prepared from the reaction of 2-amino pyridine and 4-toluenesulfonyl chloride in the presence of potassium hydroxide solution 1 M as a base and THF was used as a solvent. The complex tetrakis [N-(2-pyridyl) sulfonamide] di palladium (1) (Pd₂L₄) was also prepared from the reaction of PdCl₂(CH₃CN)₂ using (PTS) in the presence of NaOH 0.5 M and its application in Heck and Suzuki reactions. This complex consists of a binuclear unit consisting of four ligands linked to two palladium atoms via the nitrogen of pyridines ring and the nitrogen of sulfonamides. These compounds were confirmed by FT-IR and ¹H NMR spectroscopy. Moreover, the structure of the complex was studied by single-crystal X-ray diffraction method. The green crystal of Pd₂L₄ [L = N-(2-pyridyl) sulfonamide](1) was found to crystallize in the monoclinic space group C2/c with a = 18.2013(19), b = 19.7544(16), c = 17.2898(19) Å, β = 120.179(8) °; V = 5374.0(9) ų; Z = 4; the final R ₁ = 0.0894, wR ₂ = 0.1754 (or 5867 observed reflections and 318 variables). The Pd–Pd distance is 2.567(2) Å. In addition, PTS and Pd₂L₄ presented different antibacterial behaviors. The free ligand was active against Staphylococcus aureus and Escherichia coli, but the complex was inactive against them.     

Synthesis,spectroscopic characterization,crystal structures,and theoretical studies of (<Emphasis Type="Italic">E</Emphasis>)-2-(2,4-dimethoxybenzylidene)thiosemicarbazone and (<Emphasis Type="Italic">E</Emphasis>)-2-(2,5-dimethoxybenzylidene)thiosemicarbazone

Two thiosemicarbazones, (E)-2-(2,4-dimethoxybenzylidene)thiosemicarbazone (24-MBTSC (1)) and (E)-2-(2,5-dimethoxybenzylidene)thiosemicarbazone (25-MBTSC (2)), derived from 2,4-dimethoxybenzaldehyde and 2,5-dimethoxybenzaldehyde, respectively, with thiosemicarbazide have been synthesized and their structures were characterized by elemental analyses, FT-IR, ¹H NMR spectroscopy, and X-ray single-crystal diffraction analysis. Molecular orbital calculations have been carried out for 1 and 2 by using an ab initio method (HF) and also density functional method (B3LYP) at 6-31G basis set. Compound 1 crystallizes in the monoclinic system, space group P2₁/c, with a = 8.1342(5) Å, b = 18.1406(10) Å, c = 8.2847(6) Å, β = 109.7258(17)°, V = 1150.75(12) Å³, and Z = 4, whereas compound 2 crystallizes in the orthorhombic system, space group Pbca, with a = 11.0868(6) Å, b = 13.1332(6) Å, c = 15.9006(8) Å, V = 2315.2(2) Å³, and Z = 8. The compounds 1 and 2 displays a trans-configuration about the C=N double bond.     

Synthesis,structural, and electrochemical properties of NaCo(PO<Subscript>3</Subscript>)<Subscript>3</Subscript> cathode for sodium-ion batteries

A new Co-base sodium metaphosphate compound, NaCo(PO₃)₃, has been synthesized here by solid-state method. The crystal structure is refined by the Rietveld method, and the results reveal that NaCo(PO₃)₃ has an orthorhombic structure with the space group of P2 ₁ 2 ₁ 2 ₁ and lattice parameters of a = 14.2453(2) Å, b = 14.2306(1) Å, and c = 14.2603(2) Å. Its typical morphology and chemical composition are confirmed by scanning electron microscopy (SEM) and energy-dispersive spectrometry (EDS). The valence states of all elements and the internal/external vibrational modes of NaCoP₃O₉ compound are measured by X-ray photoelectron and vibrational spectrum, where a typical feature of the (PO₃)^? polyanion group is observed. Meanwhile, the electrochemical properties of NaCo(PO₃)₃ cathode for sodium-ion batteries are also elevated and an initial discharge capacity of 33.8 mAh/g can be obtained at 0.05 C within 1.5–4.2 V. After 20 cycles, a discharge capacity of 26.7 mAh/g can be obtained and a well-kept oxidation–reduction plateau is still observed for NaCo(PO₃)₃ cathode, indicating the good reversibility of this metaphosphate electrode.     

Synthesis,crystal structure of a new tetranuclear Ni<Stack><Subscript>2</Subscript><Superscript>II</Superscript></Stack>Cu<Stack><Subscript>2</Subscript><Superscript>II</Superscript></Stack> complex containing a macrocyclic ligand

The first inorg/organic hybrid complex incorporating the macrocyclic oxamide, of formula [(NiL)₂Cu₂(μ-NSC)₂(NSC)₂] (1), (NiL, H₂L = 2, 3-dioxo-5,6,14,15-dibenzo-1,4,8,12-tetraazacyclo-pentadeca-7,13-dien), have been synthesized and structurally characterized. The crystals crystallize in the triclinic system, space group P-1, for (1) a = 8.319(3) Å, b = 10.434(4) Å, c = 14.166(5) Å, a = 107.030(5)°, β  =  91.257(5)°, γ = 107.623(5)°. The complex involved both bridging N, S-ligand, and oxamide ligand, C–H?S interactions and NCS → Ni weak coordination interactions making the complex superamolecular.     

Structural and vibrational investigation of 1, 2-<Emphasis Type="Italic">bis</Emphasis>(3, 4-dimethoxyphenyl) ethane-1, 2-dione (Veratril): experimental and theoretical studies

The molecular and crystal structures of 1,2-bis(3,4-dimethoxyphenyl)ethane-1,2-dione (TMBZ = tetramethoxybenzil) were determined by a single-crystal X-ray diffraction, ¹H NMR, and FT-IR spectroscopy. The compound TMBZ (C₁₈H₁₈O₆, M _r = 330.32) crystallized in the orthorhombic Fdd2 space group wherein: a = 39.145(4), b = 18.167(2), c = 4.3139(5) Å and β = 90°, Z = 8. The packing of the molecules in the crystal lattice is stabilized by intermolecular C–H?O contacts in the herringbone arrangement. The molecular geometry and harmonic frequencies of TMBZ in the ground state were calculated utilizing density functional (B3LYP) method with the 6-311++G(d, p)-basis set. The density functional theory optimized the geometric structure, and vibrational wave numbers of TMBZ in gas phase were compared with the experimental data. A complete assignment of the fundamentals was proposed based on the total energy distribution calculation.     

New hybrids of clozapine and haloperidol and their isosteric analogues: synthesis,X-ray crystallography,conformational analysis and preliminary pharmacological evaluation

Schizophrenia is a debilitating mental disorder which affects approximately 1% of the world’s population. Clozapine is an atypical antipsychotic showing unmatched effectiveness in the control of treatment-resistant schizophrenia. Unlike typical antipsychotics, clozapine does not induce extrapyramidal side effects (EPS), tardive dyskinesia or elevate prolactin levels. However, clozapine can induce a potentially fatal blood disorder, agranulocytosis, in 1–2% of patients, severely limiting its clinical use. The model for antipsychotic activity under investigation is based on obtaining a clozapine-like profile with preferential dopamine D₄ and serotonin 5-HT_2A receptor affinity. Profiled herein are three unique members of a series of prospective antipsychotic agents. Compound (I) originated from the structural hybridization of the commercial therapeutics, clozapine and haloperidol, whilst compounds (II) and (III) possess an alternative tricyclic nucleus derived from JL13; a clozapine-like atypical antipsychotic developed by Liégeois et al. These compounds have been synthesized and characterized by means of elemental analysis, IR, ¹H and ¹³C-NMR spectroscopy, MS and X-ray diffraction. Compound (I) crystallizes in space group P(?1) with a = 10.5032(1), b = 10.6261(2), c = 12.6214(3) Å, α = 81.432(1)°, β = 83.292(1)°, γ = 61.604(1)°, Z = 2, V = 1223.62(4) Å³, C₂₈H₂₉ClN₄O, M _r = 473.00, D _c = 1.284 Mg/m³, μ = 0.185 mm^?1, F(000) = 500, R = 0.0506 and wR = 0.1304. Compound (II) crystallizes in the monoclinic space group P2₁/c with a = 10.8212(2), b = 9.3592(2), c = 22.9494(5) Å, β = 106.471(1)°, Z = 4, V = 2228.88(8) Å³, C₂₅H₂₅ClN₄O₂, M _r = 448.94, D _c = 1.338 Mg/m³, μ = 0.202 mm^?1, F(000) = 944, R = 0.0529 and wR = 0.1129. Compound (III) crystallizes in the monoclinic space group P2₁/c with a = 10.5174(2), b = 9.3112(2), c = 24.2949(5) Å, β = 98.666(1)°, Z = 4, V = 2352.03(8) Å³, C₂₅H₂₄Cl₂N₄O₂, M _r = 483.38, D _c = 1.365 Mg/m³, μ = 0.306 mm^?1, F(000) = 1008, R = 0.0478 and wR = 0.1067. The solid state conformations of (I), (II) and (III) exhibit the characteristic V-shaped buckled nature of the respective dibenzodiazepine and pyridobenzoxazepine nuclei with the central seven-membered heterocycle in a boat conformation. The molecules of (I) form a head-to-tail dimeric motif stabilized by hydrogen bonding. The results of a conformational analysis of compounds (I)–(III) investigating the effect of environment (in vacuo and aqueous solution) are presented. These analogues were tested for in vitro affinity for the dopamine D₄ and serotonin 5-HT_2A receptors and their comparative receptor binding profiles to clozapine and JL13 are reported.