Preliminary structure-activity relationship studies on some novel s-substituted aliphatic analogues of 5-{1-[(4- chlorophenyl) sulfonyl]-3-piperidinyl}-1, 3, 4-oxadiazol-2-yl sulfide

Purpose: To study the structure-activity relationships of synthetic multifunctional sulfides through evaluation of lipoxygenase and anti-bacterial activities. Methods: S-substituted derivatives of the parent compound 5-(1-(4-chlorophenylsulfonyl) piperidin-3- yl)-1, 3, 4-oxadiazole-2-thiol were synthesized through reaction with different saturated and unsaturated alkyl halides in DMF medium, with NaH catalyst. Spectral characterization of each derivative was carried out with respect to IR, 1H - NMR, 13C - NMR and EI - MS. The lipoxygenase inhibitory and antibacterial activities of the derivatives were determined using standard procedures. Results: Compound 5e exhibited higher lipoxygenase inhibitory potential than the standard (Baicalein®), with % inhibition of 94.71 ± 0.45 and IC50 of 20.72 ± 0.34 μmoles/L. Compound 5b showed significant antibacterial potential against all the bacterial strains with % inhibition ranging from 62.04 ± 2.78, 69.49 ± 0.41, 63.38 ± 1.97 and 59.70 ± 3.70 to 78.32 ± 0.41, while MIC ranged from 8.18 ± 2.00, 10.60 ± 1.83, 10.84 ± 3.00, 9.81 ± 1.86 and 11.73 ± 5.00 μmoles/L for S. typhi, E. coli, P. aeruginosa, B. subtilis and S. aureus, respectively. Compounds 5d, 5e and 5g showed good antibacterial activity against S. typhi and B. subtilis bacterial strains. Conclusion: The results suggest that compound 5e bearing n-pentyl group is a potent lipoxygenase inhibitor, while compound 5b with n-propyl substitution is a strong antibacterial agent. In addition, compounds 5d, 5e and 5g bearing n-butyl, n-pentyl and n-octyl groups, respectively, are good antibacterial agents against S. typhi and B. subtilis.

S-Alkylated/aralkylated 2-(1H-indol-3-yl-methyl)-1,3,4- oxadiazole-5-thiol derivatives. 1. Synthesis and characterization

Purpose: To synthesize and characterize S-alkylated/aralkylated 2-(1H-indol-3-ylmethyl)-1,3,4- oxadiazole-5-thiol derivatives. Methods: 2-(1H-indol-3-yl)acetic acid (1) was reacted with absolute ethanol and catalytic amount of sulfuric acid to form ethyl 2-(1H-indol-3-yl)acetate (2) which was transformed to 2-(1H-indol-3- yl)acetohydrazide (3) by refluxing with hydrazine hydrate in methanol. Ring closure reaction of 3 with carbon disulfide and ethanolic potassium hydroxide yielded 2-(1H-indol-3-ylmethyl)-1,3,4-oxadiazole-5- thiol (4) which was finally treated with alkyl/aralkyl halides (5a-u) in DMF and NaH to yield Salkylated/ aralkylated 2-(1H-indol-3-ylmethyl)-1,3,4-oxadiazole-5-thiols (6a-u). Structural elucidation was done by IR, 1H-NMR and EI-MS techniques Results: 2-(1H-indol-3-ylmethyl)-1,3,4-oxadiazole-5-thiol (4) was synthesized as the parent molecule and was characterized by IR and the spectrum showed peaks resonating at (cm-1) 2925 (Ar-H), 2250 (S-H ), 1593 (C=N ) and 1527 (Ar C=C ); 1H-NMR spectrum showed signals at δ 11.00 (s, 1H, NH-1ʹ), 7.49 ( br.d, J = 7.6 Hz, 1H, H-4\'), 7.37 (br.d, J = 8.0 Hz, 1H, H-7\'), 7.34 (br.s, 1H, H-2\'), 7.09 (t, J = 7.6 Hz, 1H, H-5\'), 7.00 (t, J = 7.6 Hz, 1H, H-6\') and 4.20 (s, 2H, CH2-10ʹ). EI-MS presented different fragments peaks at m/z 233 (C11H9N3OS)˙+ [M+2]+, 231 (C11H9N3OS)˙+ [M]+, 158 (C10H8NO)+, 156 (C10H8N2)˙+, 130 (C9H8N)+. The derivatives (6a-6u) were prepared and characterized accordingly. Conclusion: S-alkylated/aralkylated 2-(1H-indol-3-ylmethyl)-1,3,4-oxadiazole-5-thiols (6a-u) were successfully synthesized.

S-Alkylated/aralkylated 2-(1H-indol-3-yl-methyl)-1,3,4- oxadiazole-5-thiol derivatives. 2. Anti-bacterial, enzymeinhibitory and hemolytic activities

Purpose: To evaluate the antibacterial, enzyme-inhibitory and hemolytic activities of Salkylated/ aralkylated 2-(1H-indol-3-ylmethyl)-1,3,4-oxadiazole-5-thiol derivatives. Methods: Antibacterial activities of the compounds were evaluated using broth dilution method in 96 well plates. Enzyme inhibitory activities assays were investigated against α-glucosidase, butyrylcholinesterase (BchE) and lipoxygenase (LOX) using acarbose, eserine and baicalien as reference standards, respectively. A mixture of enzyme, test compound and the substrate was incubated and variation in absorbance noted before and after incubation. In tests for hemolytic activities, the compounds were incubated with red blood cells and variations in absorbance were used as indices their hemolytic activities. Results: The compounds were potent antibacterial agents. Five of them exhibited very good antibacterial potential similar to ciprofloxacin, and had minimum inhibitory concentrations (MIC) of at least 9.00 ± 4.12 μM against S. aureus, E.coli, and B. subtilis. One of the compounds had strong enzyme inhibitory potential against α-glucosidase, with IC50 of 17.11 ± 0.02 μg/mL which was better than that of standard acarbose (IC50 38.25 ± 0.12 μg/mL). Another compound had 1.5 % hemolytic activity. Conclusion: S-Alkylated/aralkylated 2-(1H-indol-3-ylmethyl)-1,3,4-oxadiazole-5-thiol deviratives with valuable antibacterial, anti-enzymatic and hemolytic activities have been successfully synthesized. These compounds may be useful in the development of pharmaceutical products.

Theory and optimisation of 1.3 and 1.55 μm (Al)InGaAs metamorphic quantum well lasers

The use of InGaAs metamorphic buffer layers (MBLs) to facilitate the growth of lattice-mismatched heterostructures constitutes an attractive approach to developing long-wavelength semiconductor lasers on GaAs substrates, since they offer the improved carrier and optical confinement associated with GaAs-based materials. We present a theoretical study of GaAs-based 1.3 and 1.55 μm (Al)InGaAs quantum well (QW) lasers grown on InGaAs MBLs. We demonstrate that optimised 1.3 μm metamorphic devices offer low threshold current densities and high differential gain, which compare favourably with InP-based devices. Overall, our analysis highlights and quantifies the potential of metamorphic QWs for the development of GaAs-based long-wavelength semiconductor lasers, and also provides guidelines for the design of optimised devices.

Bland rutschbanebrallor och halkiga stockar : En studie om hur förskollärare tillsammans med barnen arbetar utomhus med fysikaliska begrepp som återkommer i läroplanen för åk 1-3.

The purpose of this study was to find out if preschool teachers use physical concepts included in thecurriculum for grade 1-3 (gravity, center of gravity, equilibrium, balance and friction) with the children in the outdoor environment at the preschool, if preschool teachers believe it is concepts that works to use with children in preschool outdoor environment and if the work could be developed regarding these physical concepts. To conduct the study, observations were done of preschool yards and semi-structured interviewswere conducted with preschool teachers who work in preschool right now. The result shows that it requires little resources to work with these concepts outdoors and teachers are positive to use the concepts but they do not use it to the extent they would like for a variety of reasons. In various ways, the preschool teachers also expresses that it is possible for children to absorb the physical concepts at preschool and it would help to later build a foundation in the form of childrens thinking that science is something fun and exciting that belong in their everyday lives.

Undervisningsmetoder inom läsförståelse i teori och praktik. : Sex lärares uppfattningar och konkreta arbete gällande undervisningen inom läsförståelse i årskurs 1-3.

Resultaten av de internationella undersökningarna PISA 2011 och PIRLS 2011 visar att de svenska elevernas resultat inom läsförståelse försämrats. I Skolinspektionen granskning framkommer det att diskussioner och textsamtal har en relativt liten del av undervisningen av läsförståelse i Sverige idag. Tidigare forskning har ringat in fyra metoder som anses effektivast för elevers utveckling av läsförståelse. Textsamtal, diskussioner och reflektioner har avgörande roller inom alla fyra undervisningsmetoder. Syftet med denna studie är att synliggöra hur sex lärare tänker kring, samt konkret arbetar med, undervisningen av läsförståelse, för att se om de fyra metoderna går att återfinna i de sex lärarnas undervisning. Metoderna som används är semistrukturerade intervjuer samt strukturerade observationer. Resultatet av studien visar att den strategiinriktade undervisningen dominerar undervisningen bland de sex lärarna, och att innehållsorienterad undervisning, vilken visats effektivast i forskningen, är ytterst begränsad. Samtidigt beskriver samtliga lärare att samtal och diskussioner bör vara en stor del av undervisningen inom läsförståelse. En slutsats av studien är att synen på undervisningen av läsförståelse varierar mellan de sex lärarna, samt att allt undervisningsmaterial är baserat på läsförståelsestrategier. Dock förekommer knappt diskussioner och samtal i samband med undervisningen av strategier, vilket är en viktig del för att arbetet med strategiinriktad undervisning ska kunna utveckla elevernas läsförståelse på bästa sätt.

Lärares syfte med laborativt arbete i NOundervisningen i årskurs 1-3 : En kvalitativ intervjustudie om sex lärares syfte med laborativt arbete i NO-undervisningen

Syftet med denna kvalitativa studie var att undersöka lärares syfte med laborativt arbete i årskurs 1-3 i NO-undervisningen samt vilka svårigheter som lärarna beskriver med det laborativa arbetssättet i NO-undervisningen. Studien har genomförts med hjälp av kvalitativa intervjuer av sex lärare som är verksamma i årskurserna 1-3. Alla tre årskurserna finns representerade i studien. De resultat som framkommit i studien är att lärare har flera olika syftet med det laborativa arbetet i NO-undervisningen. De syften som framkom var att öka förståelsen för naturvetenskapliga fenomen hos eleverna, öka elevernas motivation och intresse för naturvetenskap, erbjuda elever att uppleva naturvetenskap med händerna, erbjuda eleverna en möjlighet att träna på läroplanens mål, erbjuda eleverna en undervisning som utgår från varje elevs förutsättningar. Studiens frågeställningar berör även hur de intervjuade lärarna använder sig av laborativt arbete samt vilka svårigheter som lärarna uppger finnas med arbetssättet. Studien visar då att lärarna främst arbetar laborativt utomhus främst med biologi och att den svårigheten som flest lärare påpekade var avsaknaden av material.

Enantioselektive Synthese von Tetrahydroprotoberberinen und anderen Benzylisochinolinalkaloiden aus alpha-Aminonitrilen

Ziel dieser Arbeit war es, ausgehend von alpha-Aminonitrilen verschiedene Tetrahydroisochinolin-Alkaloide darzustellen. Es wurde gezeigt, dass sich das alpha-Aminonitril unter kontrollierten Bedingungen quantitativ in alpha-Position deprotonieren lässt und durch anschließende C-1-Alkylierung mit substituierten Benzylbromiden zu 1 Benzyl-3,4-dihydroisochinolinen umsetzen lässt. Diese konnten im nächsten Schritt mittels asymmetrischer Transferhydrierung nach Noyori in Alkaloid-Vorläufer mit hoher optischer Reinheit umgewandelt werden. Zur Überführung der (S)-1-Benzylisochinoline in die natürlich vorkommenden Alkaloide wurden diese N-methyliert und entschützt. Auf diese Weise konnten (+)-Laudanosin, (+)-Laudanidin und (+)-Armepavin dargestellt werden. Pictet-Spengler-Cyclisierung der Benzylisochinoline erzeugte Alkaloide vom Protoberberin-Typ. Die Ullmann-Kupplung zum Aufbau der Diaryletherbrücke bildete den Schlüsselschritt bei der Darstellung von Bisbenzylisochinolinalkaloiden. Unter Verwendung von N,N-Dimethylglycin, CuI und dem Einsatz von Mikrowellen-Strahlen wurden im folgenden Schritt (+)-O-Methylthalibrin und (+)-O-Tetramethylmagnolamin in enantiomerenreiner Form und mit guten Ausbeuten dargestellt. Die Synthese von (−)-Tetrahydropalmatin unter Reaktionsbedingungen nach Pictet und Spengler über ein in C-2’ blockiertes (S)-1-Benzylisochinolin gelang nicht. Stattdessen erfolgte eine exocyclische [1,3]-Umlagerung der Benzyl-Gruppe des Iminium-Ions. Diese Umlagerung ist mit der von Knabe gefundenen endocyclischen Umlagerung von 1,2-disubstituierten 1,2-Dihydroisochinolinen verwandt. Der Nachweis über das Auftreten freier Radikale während der hier gefundenen [1,3]-Benzyl-Umlagerung erfolgte über ein Crossover-Experiment, Isotopen-Markierung sowie Studien zur Inhibierung bzw. Initiierung freier Radikale. Die experimentellen Befunde und DFT Berechnungen von Straub unterstützen die Theorie zum Verlauf über eine diffusionskontrollierte Radikal-Ketten-Reaktion.

Imidoylketene dimerization and rearrangement

FVT of pyrroledione 10 affords the NH-imidoylketene 11, which is characterized by its matrix isolation IR spectrum ( 2117 cm 1). On warming above 170 K, 11 dimerizes to the oxazinone 13, the X-ray crystal structure of which is reported. Imidoylketene 11 also undergoes a (reversible) 1,3-phenyl shift to afford the detectable alpha-oxoketenimine 16 (2062 cm(-1)) which at FVT temperatures above 400degreesC, isomerizes to 2-cyano-2-phenylacetophenone 18 (optimally at 700degreesC). Moreover, imidoylketene 11 can cyclize to azetinone 19, detectable at FVT temperatures up to 570degreesC, which undergoes cycloreversion to diphenylacetylene 20 and isocyanic acid (HNCO) 21. Energy profiles calculated at the B3LYP/6-31G** level for the unsubstituted imidoylketene, the diphenylimidoylketene 11 and the N-tert-butylimidoylketene are also reported.

Generalized atoms in molecules approach (GAIM approach)

This thesis involves two parts. The first is a new-proposed theoretical approach called generalized atoms in molecules (GAIM). The second is a computational study on the deamination reaction of adenine with OH⁻/nH₂O (n=0, 1, 2, 3) and 3H₂O. The GAIM approach aims to solve the energy of each atom variationally in the first step and then to build the energy of a molecule from each atom. Thus the energy of a diatomic molecule (A-B) is formulated as a sum of its atomic energies, EA and EB. Each of these atomic energies is expressed as, EA = Hᴬ + Vₑₑᴬᴬ + 1/2Vₑₑᴬ<>ᴮ EB = Hᴮ + Vₑₑᴮᴮ + 1/2Vₑₑᴬ<>ᴮ where; Hᴬ and Hᴮ are the kinetic and nuclear attraction energy of electrons of atoms A and B, respectively; Vₑₑᴬᴬ and Vₑₑᴮᴮ are the interaction energy between the electrons on atoms A and B, respectively; and Vₑₑᴬ<>ᴮ is the interaction energy between the electrons of atom A with the electrons of atom B. The energy of the molecule is then minimized subject to the following constraint, |ρA(r)dr + |ρB(r)dr = N where ρA(r) and ρB(r) are the electron densities of atoms A and B, respectively, and N is the number of electrons. The initial testing of the performance of GAIM was done through calculating dissociation curves for H₂, LiH, Li₂, BH, HF, HCl, N₂, F₂, and Cl₂. The numerical results show that GAIM performs very well with H₂, LiH, Li₂, BH, HF, and HCl. GAIM shows convergence problems with N₂, F₂, and Cl₂ due to difficulties in reordering the degenerate atomic orbitals Pₓ, Py, and Pz in N, F, and Cl atoms. Further work for the development of GAIM is required. Deamination of adenine results in one of several forms of premutagenic lesions occurring in DNA. In this thesis, mechanisms for the deamination reaction of adenine with OH⁻/nH₂O, (n = 0, 1, 2, 3) and 3H₂O were investigated. HF/6-31G(d), B3LYP/6-31G(d), MP2/6-31G(d), and B3LYP/6-31+G(d) levels of theory were employed to optimize all the geometries. Energies were calculated at the G3MP2B3 and CBS-QB3 levels of theory. The effect of solvent (water) was computed using the polarizable continuum model (PCM). Intrinsic reaction coordinate (IRC) calculations were performed for all transition states. Five pathways were investigated for the deamination reaction of adenine with OH⁻/nH₂O and 3H₂O. The first four pathways (A-D) begin with by deprotonation at the amino group of adenine by OH⁻, while pathway E is initiated by tautomerization of adenine. For all pathways, the next two steps involve the formation of a tetrahedral intermediate followed by dissociation to yield products via a 1,3-hydrogen shift. Deamination with a single OH⁻ has a high activation barrier (190 kJ mol⁻¹ using G3MP2B3 level) for the rate-determining step. Addition of one water molecule reduces this barrier by 68 kJ mol⁻¹ calculated at G3MP2B3 level. Adding more water molecules decreases the overall activation energy of the reaction, but the effect becomes smaller with each additional water molecule. The most plausible mechanism is pathway E, the deamination reaction of adenine with 3H₂O, which has an overall G3MP2B3 activation energy of 139 and 137 kJ mol⁻¹ in the gas phase and PCM, respectively. This barrier is lower than that for the deamination with OH⁻/3H₂O by 6 and 2 kJ mol⁻¹ in the gas phase and PCM, respectively.

Synthesis And Antiproliferative Activity Of 8-hydroxyquinoline Derivatives Containing A 1,2,3-triazole Moiety.

Twelve novel 8-hydroxyquinoline derivatives were synthesized with good yields by performing copper-catalyzed Huisgen 1,3-dipolar cycloaddition (click reaction) between an 8-O-alkylated-quinoline containing a terminal alkyne and various aromatic or protected sugar azides. These compounds were evaluated in vitro for their antiproliferative activity on various cancer cell types. Protected sugar derivative 16 was the most active compound in the series, exhibiting potent antiproliferative activity and high selectivity toward ovarian cancer cells (OVCAR-03, GI50 < 0.25 μg mL(-1)); this derivative was more active than the reference drug doxorubicin (OVCAR-03, GI50 = 0.43 μg mL(-1)). In structure-activity relationship (SAR) studies, the physico-chemical parameters of the compounds were evaluated and docking calculations were performed for the α-glucosidase active site to predict the possible mechanism of action of this series of compounds.

Potassium trifluoro[(Z)-3-methoxyprop-1-enyl]borate

In the title salt, K(+)center dot C(4)H(7)BF(3)O(-), the K atom is surrounded by six anions making close contacts through seven F [K center dot center dot center dot F = 2.779 (1)-3.048 (1) angstrom] and two O [K center dot center dot center dot O = 2.953 (2) and 3.127 (2) angstrom] atoms in a trivacant fac-vIC-9 icosahedral coordination geometry.

N-mesityl-C-acylketenimines: 1,5-sigmatropic shifts and electrocyclization to quinolines

Flash vacuum thermolysis (FVT) of triazoles 6a-c generates alpha-oxoketenimines 10, the ester 10a being isolable. FVT of pyrroledione 8 generates the isomeric imidoylketene 9a. Ketenes 9 and ketenimines 10 undergo thermal interconversion by 1,3-shifts of methoxy and dimethylamino groups under mild FVT conditions (ca. 350-400 degrees C). Both 9 and 10 are directly observable by IR spectroscopy at either 77 K or on Ar matrix isolation at 12 K. On FVT at temperatures above ca. 400 degrees C, the ketenimines 10 undergo a 1,5-H shift to o-quinoid imines 12/13, followed by electrocyclization to dihydroquinolines 14 (unobserved) and 15 (observed by NMR). The latter are easily oxidized to alkylquinoline-3-carboxylates or quinoline-3-carboxamides 16 by atmospheric oxygen. Ab initio calculations on model compounds 18-23 predict an energy barrier of ca. 38 kcal mol(-1) (161 kJ mol(-1)) for the 1,5-H shift in N-(o-methylphenyl)ketenimines via the transition state TS19 followed by an electrocyclization barrier to dihydroquinoline 23a via TS22a of ca. 16 kcal mol(-1).

Pesquisa de antigenos aglutinantes "major" 1, 2 e 3 em cepas de Bordetella pertussis, isoladas de crianças com coqueluche atendidas no Hospital de Isolamento Emílio Ribas de São Paulo, Brasil

Em 30 cepas de Bordetella pertussis isoladas de crianças com coqueluche, atendidas no Hospital de Isolamento Emílio Ribas de São Paulo, foram pesquisados os antígenos aglutinantes ''major" 1, 2 e 3. Levando-se em conta a presença combinada dos três antígenos, as provas de soro-aglutinação rápida em lamina revelaram que 25 (83,3%) cepas possuiam os fatores 1, 2 e 3, enquanto que 3 (10,0%) e 2 (6,7%) foram positivas, somente, para 1, 2 e 1, 3, respectivamente. Os resultados foram discutidos, considerando-se a importância deste antígeno no preparo de vacinas.

Synthesis, antiangiogenesis evaluation and molecular docking studies of 1-Aryl-3-[(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas: Discovery of a new substitution pattern for type II VEGFR-2 Tyr kinase inhibitors

The synthesis and biological evaluation of novel 1-aryl-3-[2-, 3- or 4-(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas 3, 4 and 5 as VEGFR-2 tyrosine kinase inhibitors, are reported. The 1-aryl-3-[3-(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas 4a-4h, with the arylurea in the meta position to the thioether, showed the lowest IC50 values in enzymatic assays (10-206 nM), the most potent compounds 4d-4h (IC50 10-28 nM) bearing hydrophobic groups (Me, F, CF3 and Cl) in the terminal phenyl ring. A convincing rationalization was achieved for the highest potent compounds 4 as type II VEGFR-2 inhibitors, based on the simultaneous presence of: (1) the thioether linker and (2) the arylurea moiety in the meta position. For compounds 4, significant inhibition of Human Umbilical Vein Endothelial Cells (HUVECs) proliferation (BrdU assay), migration (wound-healing assay) and tube formation were observed at low concentrations. These compounds have also shown to increase apoptosis using the TUNEL assay. Immunostaining for total and phosphorylated (active) VEGFR-2 was performed by Western blotting. The phosphorylation of the receptor was significantly inhibited at 1.0 and 2.5 microM for the most promising compounds. Altogether, these findings point to an antiangiogenic effect in HUVECs.