A Theoretical and Synthetic Investigation of New Donors for Organic Electro-Optic Chromophores: Understanding the Effects of Structure and Substituents on Donor Strength

Thesis (Ph.D.)--University of Washington, 2016-08

Studies on the Catalytic Asymmetric Fischer Indolization

This work describes further developments and applications of the catalytic asymmetric Fischer indolization. In the first part of this thesis, the development of an organocatalytic asymmetric synthesis of helicenes via a Fischer indolization is discussed. The application of a novel SPINOL-derived phosphoric acid, featuring extended π-surfaces as 3,3‘-substituents which can potentially participate in π-interactions with the polyaromatic intermediate, afforded the corresponding products in high yields and enantioselectivities. The second part of this work describes the development of a catalytic asymmetric dearomatizing synthesis of 1,4-diketones via an interrupted Fischer indolization. Employing aryl hydrazines with α-substituents next to the hydrazine group prevents the rearomatization which takes place in common Fischer indole syntheses, thus enabling the hydrolysis of the generated diimine species. In the presence of STRIP as catalyst, a variety of different 1,4-diketones could be obtained in generally high yields, diastereo- and enantioselectivities. The last part of this thesis deals with the development of an organocatalytic asymmetric stereodivergent synthesis of novel 3H- and 2H-pyrroles, applying an interrupted Fischer indolization and for the 2H-pyrroles a subsequent stereospecific [1,5]-alkyl shift. Employing STRIP as catalyst afforded the corresponding products in good to excellent yields and enantioselectivities. Preliminary biological investigations of these novel structure motifs in cell-based assays, monitoring biological signal transduction pathways showed an inhibition of the Hedgehog signaling pathway in a μM range.

The role of glass modifiers in the solubility of Tm3+ ions in As2S3 glasses

Au cours des années une variété des compositions de verre chalcogénure a été étudiée en tant qu’une matrice hôte pour les ions Terres Rares (TR). Pourtant, l’obtention d’une matrice de verre avec une haute solubilité des ions TR et la fabrication d’une fibre chalcogénure dopée au TR avec une bonne qualité optique reste toujours un grand défi. La présente thèse de doctorat se concentre sur l’étude de nouveaux systèmes vitreux comme des matrices hôtes pour le dopage des ions TR, ce qui a permis d’obtenir des fibres optiques dopées au TR qui sont transparents dans l’IR proche et moyenne. Les systèmes vitreux étudiés ont été basés sur le verre de sulfure d’arsenic (As2S3) co-dopé aux ions de Tm3+ et aux différents modificateurs du verre. Premièrement, l’addition de Gallium (Ga), comme un co-dopant, a été examinée et son influence sur les propriétés d’émission des ions de Tm a été explorée. Avec l’incorporation de Ga, la matrice d’As2S3 dopée au Tm a montré trois bandes d’émission à 1.2 μm (1H5→3H6), 1.4 μm (3H4→3F4) et 1.8 μm (3F4→3H6), sous l’excitation des longueurs d’onde de 698 nm et 800 nm. Les concentrations de Tm et de Ga ont été optimisées afin d’obtenir le meilleur rendement possible de photoluminescence. À partir de la composition optimale, la fibre Ga-As-S dopée au Tm3+ a été étirée et ses propriétés de luminescence ont été étudiées. Un mécanisme de formation structurale a été proposé pour ce système vitreux par la caractérisation structurale des verres Ga-As-S dopés au Tm3+, en utilisant la spectroscopie Raman et l’analyse de spectrométrie d’absorption des rayons X (EXAFS) à seuil K d’As, seuil K de Ga et seuil L3 de Tm et il a été corrélé avec les caractéristiques de luminescence de Tm. Dans la deuxième partie, la modification des verres As2S3 dopés au Tm3+, avec l’incorporation d’halogénures (Iode (I2)), a été étudiée en tant qu’une méthode pour l’adaptation des paramètres du procédé de purification afin d’obtenir une matrice de verre de haute pureté par distillation chimique. Les trois bandes d’émission susmentionnées ont été aussi bien observées pour ce système sous l’excitation à 800 nm. Les propriétés optiques, thermiques et structurelles de ces systèmes vitreux ont été caractérisées expérimentalement en fonction de la concentration d’I2 et de Tm dans le verre, où l’attention a été concentrée sur deux aspects principaux: l’influence de la concentration d’I2 sur l’intensité d’émission de Tm et les mécanismes responsables pour l’augmentation de la solubilité des ions de Tm dans la matrice d’As2S3 avec l’addition I2.

Développement de la polymérisation par (hétéro)arylation directe pour l’électronique organique

L’électronique organique suscite un intérêt grandissant en recherche grâce aux nouvelles possibilités qu’elle offre pour faciliter l’intégration de dispositifs électroniques dans nos vies. Grâce à elle, il est possible d’envisager des produits légers, flexibles et peu coûteux à produire. Les classes majeures de dispositifs étudiées sont les cellules photovoltaïques organiques (CPO) et les transistors organiques à effet de champ (TOEC). Dans les dernières années, une attention particulière a été portée sur les méthodes de polymérisation des matériaux organiques entrant dans la fabrication de ces dispositifs. La polymérisation par (hétéro)arylation directe (PHAD) catalysée au Pd offre une synthèse sans dérivé organométallique utilisant simplement un lien C-H aromatique, ce qui facilite la purification, diminue le nombre d’étapes et rend possible la production de matériaux à plus faible coût. De plus, la PHAD permet la préparation de matériaux qui était difficile, voire impossible, à obtenir auparavant. Cependant, l’inconvénient majeur de la PHAD reste sa limitation à certaines classes de polymères possédant des monomères ayant des positions bloquées favorisant qu’une seule paire de liaisons C-H. Dans le cadre de ces travaux de doctorat, l’objectif général est d’étudier la polymérisation par PHAD afin d’accéder à des classes de monomères qui n’étaient pas envisageables auparavant et à étendre l’application de cet outil dans le domaine des polymères conjugués. Plus spécifiquement, nous avons étudié l’utilisation de groupements protecteurs et partants sur des unités de benzodithiophènes et de bithiophène-silylés. Suivant ces résultats, nos travaux ont porté sur la polymérisation de dérivés de bithiophènes avec des bromo(aryle)s, une classe de polymères fréquemment utilisée en électronique organique mais qui était jugée impossible à polymériser par PHAD auparavant. Cette étude a montré l’importance de contrôler la PHAD afin d’obtenir le polymère souhaité. Finalement, nous avons étudié l’effet du système catalytique sur le taux de β−ramifications lors de la synthèse de polymères à base de thiophènes. Dans cette dernière étude, nous avons démontré l’importance d’utiliser des outils de caractérisation adéquats afin de confirmer la qualité des polymères obtenus.

Ferulates and lignin structural composition in cork

The structure of lignin and suberin, and ferulic acid (FA) content in cork from Quercus suber L. were studied. Extractive-free cork (Cork), suberin, desuberized cork (Cork(sap)), and milled-cork lignins (MCL) from Cork and Cork(sap) were isolated. Suberin composition was determined by GC-MS/FID, whereas the polymers structure in Cork, Corksap, and MCL was studied by Py-TMAH and 2D-HSQC-NMR. Suberin contained 94.4% of aliphatics and 3.2% of phenolics, with 90% of omega-hydroxyacids and alpha,omega-diacids. FA represented 2.7% of the suberin monomers, overwhelmingly esterified to the cork matrix. Py-TMAH revealed significant FA amounts in all samples, with about 3% and 6% in cork and cork lignins, respectively. Py-TMAH and 2D-HSQC-NMR demonstrated that cork lignin is a G-lignin (>96% G units), with a structure dominated by beta-O-4' alkyl-aryl ether linkages (80% and 77% of all linkages in MCL and MCLsap, respectively), followed by phenylcoumarans (18% and 20% in MCL and MCLsap, respectively), and smaller amounts of resinols (ca. 2%) and dibenzodioxocins (1%). HSQC also revealed that cork lignin is heavily acylated (ca. 50%) exclusively at the side-chain gamma-position. Ferulates possibly have an important function in the chemical assembly of cork cell walls with a cross-linking role between suberin, lignin and carbohydrates.

EXCITON ENGINEERING THROUGH TUNALBLE FLUORESCENT QUANTUM DEFECTS

This thesis demonstrates exciton engineering in semiconducting single-walled carbon nanotubes through tunable fluorescent quantum defects. By introducing different functional moieties on the sp2 lattice of carbon nanotubes, the nanotube photoluminescence is systematically tuned over 68 meV in the second near-infrared window. This new class of quantum emitters is enabled by a new chemistry that allows covalent attachment of alkyl/aryl functional groups from their iodide precursors in aqueous solution. Using aminoaryl quantum defects, we show that the pH and temperature of complex fluids can be optically measured through defect photoluminescence that encodes the local environment information. Furthermore, defect-bound trions, which are electron-hole-electron tri-carrier quasi-particles, are observed in alkylated single-walled carbon nanotubes at room temperature with surprisingly high photoluminescence brightness. Collectively, the emission from defect-bound excitons and trions in (6,5)-single walled carbon nanotubes is 18-fold brighter than that of the native exciton. These findings pave the way to chemical tailoring of the electronic and optical properties of carbon nanostructures with fluorescent quantum defects and may find applications in optoelectronics and bioimaging.

Novel Anti-Campylobacter Compounds Identified Using High Throughput Screening of a Pre-selected Enriched Small Molecules Library

Campylobacter is a leading cause of foodborne bacterial gastroenteritis worldwide and infections can be fatal. The emergence of antibiotic-resistant Campylobacter spp. necessitates the development of new antimicrobials. We identified novel anti-Campylobacter small molecule inhibitors using a high throughput growth inhibition assay. To expedite screening, we made use of a “bioactive” library of 4,182 compounds that we have previously shown to be active against diverse microbes. Screening for growth inhibition of Campylobacter jejuni, identified 781 compounds that were either bactericidal or bacteriostatic at a concentration of 200 µM. Seventy nine of the bactericidal compounds were prioritized for secondary screening based on their physico-chemical properties. Based on the minimum inhibitory concentration against a diverse range of C. jejuni and a lack of effect on gut microbes, we selected 12 compounds. No resistance was observed to any of these 12 lead compounds when C. jejuni was cultured with lethal or sub-lethal concentrations suggesting that C. jejuni is less likely to develop resistance to these compounds. Top 12 compounds also possessed low cytotoxicity to human intestinal epithelial cells (Caco-2 cells) and no hemolytic activity against sheep red blood cells. Next, these 12 compounds were evaluated for ability to clear C. jejuni in vitro. A total of 10 compounds had an anti-C. jejuni effect in Caco-2 cells with some effective even at 25 µM concentrations. These novel 12 compounds belong to five established antimicrobial chemical classes; piperazines, aryl amines, piperidines, sulfonamide and pyridazinone. Exploitation of analogues of these chemical classes may provide Campylobacter specific drugs that can be applied in both human and animal medicine.

A contribution towards the performance and structural understanding of copper and nickel salts as ammonia stores

The ongoing depletion of fossil fuels and the severe consequences of the greenhouse effect make the development of alternative energy systems crucially important. While hydrogen is, in principle, a promising alternative, releasing nothing but energy and pure water. Hydrogen storage is complicated and no completely viable technique has been proposed so far. This work is concerned with the study of one potential alternative to pure hydrogen: ammonia, and more specifically its storage in solids. Ammonia, NH3, can be regarded as a chemical hydrogen carrier with the advantages of strongly reduced flammability and explosiveness as compared to hydrogen. Furthermore, ammine metal salts presented here as promising ammonia stores easily store up to 50 wt.-% ammonia, giving them a volumetric energy density comparable to natural gas. The model system NiX2–NH3 ( X = Cl, Br, I) is studied thoroughly with respect to ammine salt formation, thermal decomposition, air stability and structural effects. The system CuX2–NH3 ( X = Cl, Br) has an adverse thermal decomposition behaviour, making it impractical for use as an ammonia store. This system is, however, most interesting from a structural point of view and some work concerning the study of the structural behaviour of this system is presented. Finally, close chemical relatives to the metal ammine halides, the metal ammine nitrates are studied. They exhibit interesting anion arrangements, which is an impressive showcase for the combination of diffraction and spectroscopic information. The characterisation techniques in this thesis range from powder diffraction over single crystal diffraction, spectroscopy, computational modelling, thermal analyses to gravimetric uptake experiments. Further highlights are the structure solutions and refinements from powder data of (NH4)2[NiCl4(H2O)(NH3)] and Ni(NH3)2(NO3)2, the combination of crystallographic and chemical information for the elucidation of the (NH4)2[NiCl4(H2O)(NH3)] formation reaction and the growth of single crystals under ammonia flow, a technique allowing the first documented successful growth and single crystal diffraction measurement for [Cu(NH3)6]Cl2.

Développement et caractérisation de dérivés dipyrrométhène pour des applications dans le domaine du photovoltaïque

Ce projet de recherche mené en collaboration industrielle avec St-Jean Photochimie Inc. / PCAS Canada vise le développement et la caractérisation de dérivés dipyrrométhène pour des applications dans le domaine du photovoltaïque. La quête du récoltage des photons se situant dans le proche-infrarouge a été au centre des modifications structurales explorées afin d’augmenter l’efficacité de conversion des cellules solaires de type organique et à pigments photosensibles. Trois familles de composés intégrant le motif dipyrrométhène ont été synthétisées et caractérisées du point de vue spectroscopique, électrochimique, structural ainsi que par modélisation moléculaire afin d’établir des relations structures-propriétés. La première famille comporte six azadipyrrométhènes au potentiel de coordination tétradentate sur des centres métalliques. Le développement d’une nouvelle voie synthétique asymétrique combinée à l’utilisation d’une voie symétrique classique ont permis d’obtenir l’ensemble des combinaisons de substituants possibles sur les aryles proximaux incluant les noyaux 2-hydroxyphényle, 2-méthoxyphényle et 2- pyridyle. La modulation du maximum d’absorption dans le rouge a pu être faite entre 598 et 619 nm. De même, la présence de groupements méthoxyle ou hydroxyle augmente l’absorption dans le violet (~410 nm) tel que démontré par modélisation. La caractérisation électrochimique a montré que les dérivés tétradentates étaient en général moins stables aux processus redox que leur contre-parti bidentate. La deuxième famille comporte dix dérivés BODIPY fusionnés de façon asymétrique en position [b]. L’aryle proximal a été modifié de façon systématique afin de mieux comprendre l’impact des substituents riches en électron et de la fusion de cycles aromatiques. De plus, ces dérivés ont été mis en relation avec une vaste série de composés analogues. Les résultats empiriques ont montré que les propriétés optoélectroniques de la plateforme sont régies par le degré de communication électronique entre l’aryle proximal, le pyrrole sur lequel il est attaché et le noyau indolique adjacent à ce dernier. Les maximums d’absorption dans le rouge sont modulables entre 547 et 628 nm et la fluorescence des composés se situe dans le proche- infrarouge. L’un des composé s’est révélé souhaitable pour une utilisation en photovoltaïque ainsi qu’à titre de sonde à pH. La troisième famille comporte cinq complexes neutres de RuII basés sur des polypyridines et portant un ligand azadipyrrométhène cyclométalé. Les composés ont montré une forte absorption de photons dans la région de 600 à 800 nm (rouge à proche- infrarouge) et qui a pu être étendue au-delà de 1100 nm dans le cas des dérivés portant un ligand terpyridine. L’analyse des propriétés optoélectroniques de façon empirique et théorique a montré un impact significatif de la cyclométalation et ouvert la voie pour leur étude en tant que photosensibilisateurs en OPV et en DSSC. La capacité d’un des complexes à photo-injecter un électron dans la bande de conduction du semi-conducteur TiO2 a été démontré en collaboration avec le groupe du Pr Gerald J. Meyer à University of North Carolina at Chapel Hill, premier pas vers une utilisation dans les cellules solaires à pigments photosensibles. La stabilité des complexes en solution s’est toutefois avérée problématique et des pistes de solutions sont suggérées basées sur les connaissances acquises dans le cadre de cette thèse.

Diversity in Catalytic Reactions of Propargylic Diazoesters

Abstract Title of Document: Diversity in Catalytic Reactions of Propargylic Diazoesters Huang Qiu, Doctor of Philosophy, 2016 Directed By: Professor Michael P. Doyle, Department of Chemistry and Biochemistry Propargylic aryldiazoesters, which possess multiple reactive functional groups in a single molecule, were expected to undergo divergent reaction pathways as a function of catalysts. A variety of transition metal complexes including rhodium(II), palladium(II), silver(I), mercury(II), copper(I and II), and cationic gold (I) complexes have been examined to be effective in the catalytic domino reactions of propargylic aryldiazoesters. An unexpected Lewis acid catalyzed pathway was also discovered by using FeCl3 as the catalyst. Under the catalysis of selected gold catalysts, propargylic aryldiazoesters exist in equilibrium with 1-aryl-1,2-dien-1-yl diazoacetate allenes that are rapidly formed at room temperature through 1,3-acyloxy migration. The newly formed allenes further undergo a metal-free rearrangement in which the terminal nitrogen of the diazo functional group adds to the central carbon of the allene initiating a sequence of bond forming reactions resulting in the production of 1,5-dihydro-4H-pyrazol-4-ones in good yields. These 1,5-dihydro-4H-pyrazol-4-ones undergo intramolecular 1,3-acyl migration to form an equilibrium mixture or quantitatively transfer the acyl group to an external nucleophile with formation of 4-hydroxypyrazoles. In the presence of a pyridine-N-oxide, both E- and Z-1,3-dienyl aryldiazoacetates are formed in high combined yields by Au(I)-catalyzed rearrangement of propargyl arylyldiazoacetates at short reaction times. Under thermal reactions the E-isomers form the products from intramolecular [4+2]-cycloaddition with H‡298 = 15.6 kcal/mol and S‡298= -27.3 cal/ (mol•degree). The Z-isomer is inert to [4+2]-cycloaddition under these conditions. The Hammett relationships from aryl-substituted diazo esters ( = +0.89) and aryl-substituted dienes ( = -1.65) are consistent with the dipolar nature of this transformation. An unexpected reaction for the synthesis of seven-membered conjugated 1,4-diketones from propargylic diazoesters with unsaturated imines was disclosed. To undergo this process vinyl gold carbene intermediates generated by 1,2-acyloxy migration of propargylic aryldiazoesters undergo a formal [4+3]-cycloaddition, and the resulting aryldiazoesters tethered dihydroazepines undergo an intricate metal-free process to form observed seven-membered conjugated 1,4-diketones with moderate to high yields.

Estudos de vias sintéticas catalíticas para benzociclo-alcanois e análogos: potenciais fármacos para doença de Alzhjeimer

A doença de Alzheimer constitui uma ameaça significativa a nível mundial. Estima-se que, mundialmente existam cerca de 35 milhões de pessoas afetadas por este tipo de demência. Os compostos contendo um esqueleto benzocicloalcanol (que incluem benzofuranos e di-hidrobenzofuranóis) mostram atividades biológicas significativas e possuem muito potencial no tratamento das doenças neurodegenerativas. Nos últimos anos têm havido avanços significativos no campo das reações catalisadas por metais. As reações de adição nucleófila intramolecular e a de Heck intramolecular constituem metodologias importantes para a síntese de benzocicloalcanóis. No âmbito deste trabalho, pretendia-se sintetizar uma biblioteca de compostos contendo um esqueleto benzocicloalcanol. A estratégia adotada para a síntese de dihidrobenzofuranóis envolveu um método de ciclização catalítica de cetonas aril-éteres e para a síntese de benzofuranos, um método de ciclização catalítico de enoatos e enamidas (amidas de Weinreb). Várias condições foram estudadas; Abstract: Studies on Synthetic Catalytic Pathways to Benzocycloalkanols and Derivatives – Potential Drugs for Alzheimer’s Disease Alzheimer's disease constitutes a significant threat worldwide. It is estimated that are about 35 million people worldwide suffering from this type of dementia. The compounds containing a benzocycloalkanol scaffold (including benzofurans and dihydrobenzofurans) show significant biological activity and have great potential in the treatment of neurodegenerative diseases. In recent years there have been many advances in the field of catalyzed reactions by transition-metals. The intramolecular nucleophilic addition and the intramolecular Heck reactions constitute important methods for the synthesis of benzocycloalkanols. Within this work, the main goal was to synthesize a library of compounds containing a benzocycloalkanol scaffold. The adopted strategy for the synthesis of dihydrobenzofurans was the catalytic cyclization of aryl ether ketones and for the synthesis of benzofurans, the catalytic cyclization of enoates and enamides (Weinreb amides). Several conditions were studied

Copper Nanoparticles in Click Chemistry

Conspectus: The challenges of the 21st century demand scientific and technological achievements that must be developed under sustainable and environmentally benign practices. In this vein, click chemistry and green chemistry walk hand in hand on a pathway of rigorous principles that help to safeguard the health of our planet against negligent and uncontrolled production. Copper-catalyzed azide–alkyne cycloaddition (CuAAC), the paradigm of a click reaction, is one of the most reliable and widespread synthetic transformations in organic chemistry, with multidisciplinary applications. Nanocatalysis is a green chemistry tool that can increase the inherent effectiveness of CuAAC because of the enhanced catalytic activity of nanostructured metals and their plausible reutilization capability as heterogeneous catalysts. This Account describes our contribution to click chemistry using unsupported and supported copper nanoparticles (CuNPs) as catalysts prepared by chemical reduction. Cu(0)NPs (3.0 ± 1.5 nm) in tetrahydrofuran were found to catalyze the reaction of terminal alkynes and organic azides in the presence of triethylamine at rates comparable to those achieved under microwave heating (10–30 min in most cases). Unfortunately, the CuNPs underwent dissolution under the reaction conditions and consequently could not be recovered. Compelling experimental evidence on the in situ generation of highly reactive copper(I) chloride and the participation of copper(I) acetylides was provided. The supported CuNPs were found to be more robust and efficient catalyst than the unsupported counterpart in the following terms: (a) the multicomponent variant of CuAAC could be applied; (b) the metal loading could be substantially decreased; (c) reactions could be conducted in neat water; and (d) the catalyst could be recovered easily and reutilized. In particular, the catalyst composed of oxidized CuNPs (Cu2O/CuO, 6.0 ± 2.0 nm) supported on carbon (CuNPs/C) was shown to be highly versatile and very effective in the multicomponent and regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles in water from organic halides as azido precursors; magnetically recoverable CuNPs (3.0 ± 0.8 nm) supported on MagSilica could be alternatively used for the same purpose under similar conditions. Incorporation of an aromatic substituent at the 1-position of the triazole could be accomplished using the same CuNPs/C catalytic system starting from aryldiazonium salts or anilines as azido precursors. CuNPs/C in water also catalyzed the regioselective double-click synthesis of β-hydroxy-1,2,3-triazoles from epoxides. Furthermore, alkenes could be also used as azido precursors through a one-pot CuNPs/C-catalyzed azidosulfenylation–CuAAC sequential protocol, providing β-methylsulfanyl-1,2,3-triazoles in a stereo- and regioselective manner. In all types of reaction studied, CuNPs/C exhibited better behavior than some commercial copper catalysts with regard to the metal loading, reaction time, yield, and recyclability. Therefore, the results of this study also highlight the utility of nanosized copper in click chemistry compared with bulk copper sources.

Synthesis and antibacterial study of some s-substituted aliphatic analogues of 2-mercapto-5-(1-(4-toluenesulfonyl) piperidin-4-yl)-1,3,4-oxadiazole

Purpose: To synthesize a series of analogues of 1,3,4-oxadiazole and to evaluate their antibacterial activity. Methods: Ethyl piperidin-4-carboxylate (1) was mixed with 4-toluenesulfonyl chloride (2) in benignant conditions to yield ethyl 1-(4-toluenesulfonyl)piperidin-4-carboxylate (3) and then 1-(4- toluenesulfonyl)piperidin-4-carbohydrazide (4). Intermolecular cyclization of 4 into 2-mercapto-5-(1-(4- toluenesulfonyl) piperidin-4-yl)-1,3,4-oxadiazole (5) was obtained on reflux with CS2 in the presence of KOH. Molecule 5 was stirred with alkyl halides, 6a-i, in DMF in the presence of LiH to synthesize the final compounds, 7a-i. The structures of these molecules were elucidated by Fourier transform infra-red (FTIR) spectroscopy, proton nuclear magnetic resonance (1H-NMR) and electron impact mass spectrometry (EI-MS). Antibacterial activity was evaluated against five bacterial strains, namely, Salmonella typhi, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilis, with ciprofloxacin used as standard antibacterial agent. Results: Out of nine synthesized derivatives, compound 7a was the most active against three bacterial strains, S. typhi, E. coli and P. aeruginosa, with minimum inhibitory concentration (MIC) of 9.11 ± 0.40, 9.89 ± 0.45 and 9.14 ± 0.72 μM, respectively, compared with 7.45 ± 0.58, 7.16 ± 0.58 and 7.14 ± 0.18 μM, respectively, for the reference standard (ciprofloxacin). Similarly, compounds 7a - 7c showed relatively good antibacterial activity against B. subtilis strain while compound 7e - 7g revealed good results against S. typhi bacterial strain. Conclusion: The results indicate that S-substituted derivatives of the parent compound are more effective antibacterial agents than the parent compound, even with minor differences in substituents

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.