New serotonin 5-HT(6) ligands from common feature pharmacophore hypotheses

Serotonin 5-HT6 receptor antagonists are thought to play an important role in the treatment of psychiatry, Alzheimer's disease, and probably obesity. To find novel and potent 5-HT6 antagonists and to provide a new idea for drug design, we used a ligand-based pharmacophore to perform the virtual screening of a commercially available database. A three-dimensional common feature pharmacophore model was developed by using the HipHop program provided in Catalyst software and was used as a query for screening the database. A recursive partitioning (RP) model which can separate active and inactive compounds was used as a filtering system. Finally a sequential virtual screening procedure (SQSP) was conducted, wherein both the common feature pharmacophore and the RP model were used in succession to improve the results. Some of the hits were selected based on druglikeness, ADME properties, structural diversity, and synthetic accessibility for real biological evaluation. The best hit compound showed a significant IC50 value of 9.6 nM and can be used as a lead for further drug development.     

Cholinesterase-based dipstick assay for the detection of organophosphate and carbamate pesticides

A cholinesterase (ChE)-based dipstick-type assay for the class-specific detection of organophosphate (OP) and carbamate (CM) pesticides was developed. The principle of the assay is based on inhibition of the activity of a ChE by these two families of pesticides, which is dependent on the concentration of pesticides. The proposed assay system is composed of a test strip with an acetylcholinesterase (AChE)-coated membrane and an enzyme substrate solution. The assay protocol involves incubation of the enzyme-coated strip in the pesticide-containing sample solution followed by incubation of the sample-treated strip in a chromogenic enzyme substrate solution. The color intensity is estimated by the naked eye or a reflectometer. Of the membranes tested as the enzyme support, Hybond N⁺ was the most suitable. Among the compounds tested as the enzyme substrate, indophenyl acetate was the best. The detectable concentration range of the dipstick assay for the OP and CM pesticides was 10⁻⁶-10² and 10⁻⁶-10⁰ μg mL⁻¹, respectively. The sensitivity of the dipstick assay to the oxidized form of parathion (paraoxon) was higher than to parathion. The strip showed a large matrix effect with pesticide-spiked lettuce samples, whereas it showed a small matrix effect with pesticide-spiked rice samples.     

Study of pH-dependent charges of soils by surface acid-base properties

The pH-dependent charges of Hungarian soils have been studied via surface acid-base properties. The intrinsic stability constants of protonation and deprotonation processes, as well as the concentration of surface sites, have been determined by surface complexation modeling. The protonation and deprotonation constants have been nearly the same for most soils. There is a relation between the concentration of surface sites and composition, expect for the freshly deposited soils with high primary silicate content. The results show that the concentrations of silanol and aluminol sites are different for each soil, the intrinsic stability constants of protonation and deprotonation processes, however, are nearly the same within experimental error. This can only be explained if these stability constants are real thermodynamic equilibrium constants. The fact that these constants are nearly the same supports the conclusion that we succeeded in excluding all processes that would disturb the measurements. The parameters characteristic of the edge sites of the soils are of two types: (a) the parameters depending on the quality and composition of the soils, (i.e.), the concentration of surface sites; (b) the parameters depending on the thermodynamically well-defined acid-base processes, independent of soil composition.     

Effect of the Linking Structure of Nonlinear Optical Side Groups on the Phase Behavior of an Aromatic Polyester Backbone

Summary: The phase behavior of poly(p‐phenylene terephthalate)s (PPT) with pendant side groups, N‐(4‐nitrophenyl)ethylaminoethanol (NPE) and N‐(4‐nitrophenyl)‐L ‐prolinol (NPP) has been studied by using differential scanning calorimetry (DSC), wide‐angle X‐ray scattering (WAXS), and second harmonic generation (SHG). PPT‐NPE showed a layered liquid crystalline morphology while PPT‐NPP showed a completely amorphous structure. Compressive or shear stress applied on the polymer melt surface at 210 °C induced a more prominent layered structure of PPT‐NPE whereas the amorphous structure of PPT‐NPP remained unchanged under the stress. In order to understand this phase difference in terms of the repeat structure, we attempted theoretical ab initio Hartree‐Fock, and DFT calculations for the monomers and molecular dynamics for the bulk state. The results indicated that molecular configurations are a good way of microscopically understanding the phases of rigid backbone polymers with functional side groups: The NPT (constant particle number, pressure, and temperature) simulation data at 210 °C agree qualitatively with the experimental data and the difference between PPT‐NPE and PPT‐NPP could be understood using rotational energy barrier, steric hindrance and inter‐chain interactions. X‐ray diffractometer (XRD) simulation patterns for the oligomers are also in qualitative agreement with the experimental WAXS data and the structural parameters of stacks of PPT‐NPE chains are estimated to be layer distance (4.6 Å), backbone distance (21.5 Å), and side distance (12 Å).

     

Composés sulfurés hétérocycliques. CII. Action de l'hydroxylamine sur les dihydro-1,2 benzothiazine-3,1 thiones-4

Hydroxylamine reacts with 1-alkyl-1,2-dihydro-3,1-benzothiazine-4thiones ( 1 ), giving 1-alky1-3-hydroxy-2,3-dihydro-1H-quinazoline-4-thiones ( 2 ). The same reagent, in neutral medium, converts 1-aryl-1,2-dihydro-3,1-benzothiazine-4-thiones ( 3 ) into 1-aryl-4-hydroxyimino-1,4-dihydro-2H-3,1-benzothiazines ( 4 ). In acidic medium, the same starting materials lead to 1-aryl-3-hydroxy-2-3-dihydro-1H-quinazoline-4-thiones ( 5 ). genrally with some quantity of the isomer 4 . Thiones 2 and 5 , as well as oximes 4 , heated at 200°, decomopose, yielding, in varying proportions, 1H-quinazoline-4-thiones ( 6 or 7 ), 1H-quinazoline-4-ones ( 9 ) and 2,3-dihydro-1H-quinazoline-4-thiones ( 11 ). Reacting with methyliodide, 1H-quinazoline-4-thiones ( 7 ) give 4-methylthioquinazolin-1-ium iodidies ( 12 ) which can be hydrolysed into 1H-quinazolin-4-ones ( 9 ). The latter are also obtained by reacting benzonitrile N-oxide with the corresponding thiones. 1-Aryl-1 H-quinazoline-4-thiones ( 7 ) react readily with nitrogen nucleophiles XNH₂ to give 1-aryl-4-imino-1,4-dihydro-quinazolines diversely substituted on the imino group. While thiones 7 are S- methylated by methyl iodide, the corresponding 1-aryl-1H-quinazolin-4-ones (9), with the same reagent, ungergo a N-methylation, yielding 1-aryl-3-methyl-4-oxo-3,4-dihydroquinazolin-l-ium iodides ( 18 ). Structure have been confirmed by uv, ir and nmr spectra.     

A question about maximal non-valuation subrings

In this paper we pursue and deep the study of ring extensions \({R \subset S}\) such that R is a maximal non-valuation subring of S [Ben Nasr and Jarboui in Houston J Math, 2009 (in press)]. It is proved in Ben Nasr and Jarboui [Houston J Math, 2009 (in press), Theorem 3.2] that if R is integrally closed with finite Krull dimension, then R is a maximal non-valuation subring of qf (R) iff R is not local and |[R, qf (R)]| = dim(R) + 3. This result encourages us to pose the following question: Let n be a nonzero positive integer greater than 2 and let R be a finite-dimensional domain such that |[R, qf (R)]| = dim(R) + n, does there exists an overring S of R such that R is a maximal non-valuation subring of S? This paper deals mostly with this question. We solve this question in case R is integrally closed.     

U(SMes*)n, (n = 3, 4) and Ln(SMes*)3 (Ln = La, Ce, Pr, Nd): lanthanide(III)/actinide(III) differentiation in agostic interactions and an unprecedented eta3 ligation mode of the arylthiolate ligand, from X-ray diffraction and DFT analysis

Reaction of U(NEt(2))(4) with HS-2,4,6-(t)Bu(3)C(6)H(2) (HSMes) gave U(SMes)(3)(NEt(2))(py) (1), whereas similar treatment of U[N(SiMe(3))SiMe(2)CH(2)][N(SiMe(3))(2)](2) afforded U(SMes)[N(SiMe(3))(2)](3) (2) and U(SMes)(3)[N(SiMe(3))(2)]. The first neutral homoleptic uranium(IV) thiolate to have been crystallographically characterized, U(SMes)(4) (4), was isolated from the reaction of U(BH(4))(4) and KSMes. The first homoleptic thiolate complex of uranium(III), U(SMes)(3) (5), was synthesized by protonolysis of U[N(SiMe(3))(2)](3) with HSMes in cyclohexane. The crystal structure of 5 exhibits the novel eta(3) ligation mode for the arylthiolate ligand. Comparison of the crystal structure of 5 with those of the isomorphous lanthanide congeners Ln(SMes)(3) (Ln = La, Ce, Pr, and Nd) indicates that the U-S, U-C(ipso)(), and U-C(ortho)() bond lengths are shorter than the corresponding ones in the 4f-element analogues, when taking into account the variation in the ionic radii of the metals. The distance between the uranium and the carbon atoms involved in the U...H-C epsilon agostic interaction of each thiolate ligand is shorter, by approximately 0.05 A, than that expected from a purely ionic bonding model. The lanthanide(III)/actinide(III) differentiation was analyzed by density functional theory (DFT). The nature of the M-S bond is shown to be ionic strongly polarized at the sulfur for M = U and iono-covalent (i.e. strongly ionic with low orbital interaction), for M = Ln. The strength of the U...H-C epsilon agostic interaction is proposed to be controlled by the maximization of the interaction between U(+) and S(-) under steric constraints. The eta(3) ligation mode of the arylthiolate ligand is also obtained from DFT.