<p>Bicyclic dihydrothiazolo fused 2-pyridones have been studied as a new class of antibacterial agents, termed pilicides, that target the formation of adhesive bacterial surface organelles (pili) in pathogenic bacteria. Synthetic methods to further functionalize the bicyclic 2-pyridone scaffold have been developed in order to increase water-solubility and thereby facilitate biological evalua-tions. This was accomplished by introducing aminomethylenes at the open position C-6. Tertiary amines were introduced via a microwave–assisted Mannich reaction and a synthetic route based on a formyl intermediate gave access to primary, secondary and tertiary amines, but also to other interesting functionalities. Biological evaluation confirmed that several of the function-alized compounds inhibited pili formation in uropathogenic <i>E. coli</i>., as dem-onstrated by assays of hemagglutination, biofilm formation and adherence to bladder cells. Co-crystallizing one of the pilicides with the target protein gave information about the binding site and based on this a mechanism of action was proposed, which was supported experimentally by surface plas-mon resonance and single point mutations in the protein.</p><p>Furthermore, the previously developed acylketene imine reaction used to prepare bicyclic thiazolo fused 2-pyridone pilicides has been developed to allow preparation of other ring-fused 2-pyridone systems. Benzo[a]quinolizine-4-ones and indolo[2,3-a]quinolizine-4-ones could be prepared in a fast and simple manner starting from dihydroisoquinolines and a β-carboline. Finally, this method could also be applied for the preparation of heteroatom analogs of the previously studied sulfur containing pilicides. Biological evaluations established that the sulfur atom can be replaced by oxygen and still maintain the ability to prevent pili assembly.</p>

<p>This thesis describes the design and synthesis of compounds that are</p><p>intended to inhibit serine and aspartic proteases. The first part of the text deals with preparation of inhibitors of the hepatitis C virus (HCV) NS3 serine protease. Hepatitis C is predominantly a chronic disease that afflicts about 170 million people worldwide. The NS3 protease, encoded by HCV, is essential for replication of the virus and has become one of the main targets when developing drugs to fight HCV. The inhibitors discussed here constitute surrogates for the widely used <em>N</em>-acyl-hydroxyproline isostere designated 4-hydroxy-cyclopentene. The stereochemistry of the 4-hydroxy-cyclopentene scaffold was determined by nuclear overhauser effect spectroscopy (NOESY) and the regiochemistry by heteronuclear multiple bond correlation (HMBC). The scaffold was decorated with different substituents to obtain both linear and macrocyclic HCV NS3 protease inhibitors that display low nanomolar activity. The second part of the thesis describes the design and synthesis of potential aspartic protease inhibitors. The hydroxyethylene motif was used as a noncleavable transition state isostere. The synthetic route yielded a pivotal intermediate with excellent stereochemical control, which was corroborated by NOESY experiments. This intermediate can be diversified with different substituents to furnish novel aspartic protease inhibitors.</p> / Report code: LIU-TEK-LIC-2006:45

Structure-based drug design and combinatorial chemistry play important roles in the search for new drugs, and both these elements of medicinal chemistry were included in the present studies. This thesis outlines the synthesis of protease inhibitors against thrombin and the HCV NS3 protease, as well as the synthesis of a combinatorial library using solid phase chemistry.In the current work potent thrombin inhibitors were generated based on the D-Phe-Pro-Arg motif incorporating cyclopentene and cyclohexene scaffolds that were synthesized by ring-closing metathesis chemistry. A structure-activity relationship study was carried out using the crystallographic results for one of the inhibitors co-crystallized with thrombin. HCV NS3 protease inhibitors comprising the proline bioisostere 4-hydroxy-cyclopent-2-ene-1,2-dicarbboxylic acid were synthesized displaying low nanomolar activity. The stereochemistry and regiochemistry of the scaffolds were determined by NOESY and HMBC spectra, respectively. The final diastereomeric target compounds were isolated and annotated by applying TOCSY and ROESY NMR experiments. Furthermore, a 4-phenyl-2-carboxypiperazine targeted combinatorial chemistry library was synthesized to be used early in the lead discovery phase. This was done using a scaffold that was synthesized by palladiumcatalyzed aromatic amination chemistry and subsequently derivatized with eight electrophiles and ten nucleophiles.

Despite the unfavorable pharmacokinetic properties associated with peptides, they are still of great interest in drug development due to a multitude of interesting biological functions. The development of peptidomimetics strives to maintain or improve the biological activity of a peptide concurrently with removing the unwanted properties. This thesis describes two synthetic approaches to peptidomimetics with particular emphasis on secondary structure mimetics. First the design, synthesis and evaluation of two beta-turn mimetics incorporated in the endorphin Leu-enkephalin is presented. The beta-turn mimetics were stabilized by replacement of the intramolecular hydrogen bond with an ethylene bridge, and the amide bond between Tyr and Gly was replaced with an ether linkage. Linear analogues of the two mimetics were also synthesized. The peptidomimetics and their linear analogues were evaluated in a competitive binding assay at two opiate receptors, my and delta. One of the cyclized beta-turn mimetics was found to be a delta receptor antagonist with an IC50 value of 160 nM. Second a synthetic strategy to a beta-strand mimetic using 2-fluoro-4-iodopyridine as scaffold is described. The synthesis involved a Grignard exchange reaction on the pyridine scaffold using an amino acid derivative as electrophile followed by an SNAr reaction using an amine as nucleophile. The synthesis of a tripeptidomimetic of Leu-Gly-Gly and attempts to introduce chiral building blocks at the C-terminal, as well as studies towards elongated mimetics are presented. Two additional studies deal with the synthesis of two classes of potential thrombin inhibitors based on the pyridine scaffold. The first class contain pyridine as central fragment (P2 residue) substituted with a para-amidinobenzylamine group as P1 residue and various benzoyl groups as P3 residues. Three potential thrombin inhibitors were synthesized and found to be microM inhibitors in an enzymatic assay. In the second class, the pyridine ring serves as P3 residue. This class also lacks a strongly basic group in the P1 position. A small library of eight compounds were synthesized and evaluated in the enzymatic assay. Unfortunately, these compounds lacked inhibitory activity.

This thesis describes the development of new synthetic methodologies for preparation of bioactive interesting compounds, e.g. substituted pyridines, piperidines or piparazines. Thesecompounds are synthesized from commercially available, cheap and easily prepared reagents, videlicet the reaction between Grignard reagents and heterocyclic N-oxides.  The first part of this thesis deals with an improvement for synthesis of dienal-oximes and substituted pyridines. This was accomplished by a rapid addition of Grignard reagents to pyridine N-oxides at rt. yielding a diverse set of substituted dienal-oximes. During these studies, it was observed that the obtained dienal-oxmies are prone to ring-close upon heating. By taking advantage of this, a practical synthesis of substituted pyridines was developed. In the second part, an ortho-metalation of pyridine N-oxides using Grignard reagents is discussed. The method can be used for incorporation of a range of different electrophiles, including aldehydes, ketones and halogens. Furthermore, the importance for incorporation of halogens are exemplified through a Suzuki–Miyaura coupling reaction of 2-iodo pyridine N-oxides and different boronic acids. Later it was discovered that if the reaction temperature is kept below -20 °C, the undesired ringopening can be avoided. Thus, the synthesis of 2,3-dihydropyridine N-oxide, by reacting Grignard reagents with pyridine N-oxides at -40 °C followed by sequential addition of aldehyde or ketone, was accomplished. The reaction provides complete regio- and stereoselectivity yielding trans-2,3-dihydropyridine N-oxides in good yields. These intermediate products could then be used for synthesis of either substituted piperidines, by reduction, or reacted in a Diels–Alder cycloaddtion to give the aza-bicyclo compound. In the last part of this thesis, the discovered reactivity for pyridine N-oxides, is applied on pyrazine N-oxides in effort to synthesize substituted piperazines. These substances are obtained by the reaction of Grignard reagents and pyrazine N-oxides at -78 °C followed by reduction and protection, using a one-pot procedure. The product, a protected piperazine, that easily can be orthogonally deprotected, allowing synthetic modifications at either nitrogens in a fast and step efficient manner. Finally, an enantioselective procedure using a combination of PhMgCl and (-)-sparteine is discussed, giving opportunity for a stereoselective synthesis of substituted piperazines.

Bicyclic dihydrothiazolo fused 2-pyridones have been studied as a new class of antibacterial agents, termed pilicides, that target the formation of adhesive bacterial surface organelles (pili) in pathogenic bacteria. Synthetic methods to further functionalize the bicyclic 2-pyridone scaffold have been developed in order to increase water-solubility and thereby facilitate biological evalua-tions. This was accomplished by introducing aminomethylenes at the open position C-6. Tertiary amines were introduced via a microwave–assisted Mannich reaction and a synthetic route based on a formyl intermediate gave access to primary, secondary and tertiary amines, but also to other interesting functionalities. Biological evaluation confirmed that several of the function-alized compounds inhibited pili formation in uropathogenic E. coli., as dem-onstrated by assays of hemagglutination, biofilm formation and adherence to bladder cells. Co-crystallizing one of the pilicides with the target protein gave information about the binding site and based on this a mechanism of action was proposed, which was supported experimentally by surface plas-mon resonance and single point mutations in the protein. Furthermore, the previously developed acylketene imine reaction used to prepare bicyclic thiazolo fused 2-pyridone pilicides has been developed to allow preparation of other ring-fused 2-pyridone systems. Benzo[a]quinolizine-4-ones and indolo[2,3-a]quinolizine-4-ones could be prepared in a fast and simple manner starting from dihydroisoquinolines and a β-carboline. Finally, this method could also be applied for the preparation of heteroatom analogs of the previously studied sulfur containing pilicides. Biological evaluations established that the sulfur atom can be replaced by oxygen and still maintain the ability to prevent pili assembly.

<p>Studien syftade till att genom aktionsforskning undersöka hur det kan skapas användbarhet i en e-handelslösning. Bakgrunden till detta ligger i författarnas eget antagande kring att det spelar in fler faktorer än endast användbarhet när ett gränssnitt skall skapas för en webbplats som erbjuder e-handel. Faktorerna identifierades till användbarhet, handlingsbarhet samt teori kring sambandet mellan förtrogenhet, tillit och lojalitet, ur vilka det gjordes ett urval för denna studie. Genom att sätta ihop dessa faktorer skapades en egen designteori, kallad e-handelsbarhet. E-handelsbarhet applicerades på en webbplats med e-handel i syfte att utföra en praktisk omarbetning av ett existerande gränssnitt. Detta utfördes genom heuristisk utvärdering samt en kontrollista och blev därigenom en applicerad designmetod. Utöver detta genomfördes användartester i syfte att empiriskt påvisa att designteorin hittade problem med gränssnittet och därav praktiskt fungerar. Användartester utfördes även för att finna ytterligare problem utöver de som designteorin hittade. Resultatet av den heuristiska utvärderingen och kontrollistan var ett antal problem med gränssnittet. De problem som designteorin samt användartester hittade åtgärdades efter samma designteori och resulterade därigenom i ett förbättrat gränssnitt på e-handelswebbplatsen. Resultatet presenteras i form av statiska mockuper på gränssnittet. Den frågeställning och problemformulering som ställdes uppfylldes via den definition av användbarhet som gjordes utifrån den egna designteorin.</p>

Peptidoglycan (PGN) är en bakteriecellväggskomponent och känd för att känna igen olika receptorer eller enzymer för att leda aktiveringsimmunsystemet. Den allmänna strukturen för PGN består av sockerkedjor inklusive N-acetylglutamin (GlcNAc), N-acetylmuraminsyra (MurNAc) och tvärbundna peptidkedjor. PGN-fragment med D-Lac-ändpeptider har hittats från vankomycinresistenta enterokocker men ett kemiskt syntetiserat PGN-fragment med en D-Lac-ändpeptid har inte undersökts i detalj. Således fokuserade vi på syntesen av PGN-fragmentstrukturer som inkluderar en D-Ala-D-Lac-rest vid den terminala delen av peptidkedjan. För att syntetisera dessa fragmentstrukturer planerade vi att kombinera fastfassyntes (för Lac-peptiddelen) och lösningsfassyntes (för glykanberedning och kondensation). Detta tillvägagångssätt är fördelaktigt för framställning av peptidoglykanfragment med en komplex grenad peptiddel. Först beredde vi sockerdelen MurNAc-derivatet i lösningsfassyntes från ett glukosderivat. Medan den Lac-innehållande peptiden framställdes med fastfas-peptidsyntes med användning av 2-klortritylkloridharts. Med denna förening gav kondensationen av dessa två föreningar det önskade D-Lac-avslutade peptidoglykanfragmentet. / Peptidoglycan (PGN) is a bacterial cell wall component and known to be recognized by various receptors or enzymes to lead the activation immune system. The general structure of PGN consists of sugar chains including N-acetylglutamine (GlcNAc), N-acetylmuramic acid (MurNAc) and cross-linked peptide chains. PGN fragments having D-Lac terminus peptides have been found from vancomycin-resistant enterococcus, but a chemically synthesized PGN fragment having a D-Lac terminus peptide has not been examined in detail. Thus, we focused on the synthesis of PGN fragment structures that include a D-Ala-D-Lac residue at the terminal part of the peptide chain. In order to synthesize these fragment structures, we planned to combine solid-phase synthesis (for the peptide- Lac part) and solution-phase synthesis (for glycan preparation and the condensation). This approach is advantageous for the preparation of peptidoglycan fragments having complex branched peptide moiety. First, we prepared the sugar moiety MurNAc derivative in solution-phase synthesis from a glucose derivative. While, the Lac-containing peptide was prepared with solid-phase peptide synthesis using 2-chlorotrityl chloride resin. Having this compound, the condensation of these two compounds gave the desired D-Lac-terminated peptidoglycan fragment.

Detta examensarbete beskriver optimering av ett katalytiskt protokoll för framställning av bisguaiacol F, ett ofarligt alternativ till bisphenol A. Lewissyrliga grupp IV metallkomplex med triflatligander användes som katalysatorer under milda betingelser och kinetisk analys användes för att underlätta optimeringen av reaktionsprotokollet för att öka utbyte och selektivitet för transformationen. Dessutom bidrog kinetiken med mekanistiska insikter och avslöjade att den nukleofila attacken starkt påverkar reaktionens selektivitet och utbyte. / This thesis describes the optimization of catalytic protocol for the formation of bisguaiacol F, a benign alternative to bisphenol A. Lewis acidic group IV metal complexes bearing triflate ligands were used as catalysts under mild conditions and kinetic analysis was used to aid optimization of the reaction protocol to increase the yield and selectivity of the transformation. In addition, the kinetics shed light on the operating mechanisms and revealed that competition of nucleophiles greatly impact selectivity and yield of the reaction.

I detta arbete så har en uppsättning aromatiska ditiol-ligander framställts (3,5-dimerkaptobensoesyra I, methyl-3,5-dimerkaptobensoat II, 3,5-dimerkaptotoluen III, 4,6-dimerkaptoisoftalaldehyde IV). En trestegssyntes innehållande Newman-Kwart omlagring som nyckelsteg användes för framställning av föreningarna I-III medan förening IV togs fram via en annan syntesväg. De fyra föreningarna syntetiserades I relativt bra utbyte (5-80% över 3, 4 eller 6 steg) och karaktäriserades med hjälp av 1H-NMR, 13C-NMR, och högupplösande masspektrometri. I en framtida fortsättning av projektet så kommer föreningarna I-IV användas som organiska ligander i koordinationspolymerer, vilka kommer karaktäriseras i termer av elektriska och termiska egenskaper. / In this work, a family of aromatic dithiol ligands were synthesized in the laboratory (3,5-dimercapto benzoic acid I, methyl 3,5-dimercapto benzoate II, 3,5-dimercapto toluene III, 4,6-dimercaptoisophthalaldehyde IV). A three-step synthesis strategy, involving the Newman-Kwart rearrangement as key step, for the formation of I, II and III was used, whereas compound IV required a different synthetic route. The four compounds were synthesized with relatively good yields (5-80% over 3, 4 or 6 steps) and were fully characterized using 1H-NMR, 13C-NMR, and high-resolution mass spectrometry. In a future extension of this work, compounds I-IV will be used as organic ligands in coordination polymers (CPs), which will be characterized in terms of electric and thermal properties.