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Doctor of Philosophy / Department of Chemistry / Christer B. Aakeröy / Co-crystallization allows the manipulation of physical properties of a given compound without affecting its chemical behavior. The ability to predict hydrogen bonding interactions, provides means to the rational design of supramolecular architectures. It also makes it possible to select with a degree of accuracy, a few co-formers that have a high probability of forming co-crystals with a compound of interest, instead of blindly screening against a large number of candidates. To study the effects of changing electronic environment on the ability to form co-crystals, five symmetric dioximes of different hydrogen bond donating ability were synthesized with different functional groups on the carbon α to the oxime moiety. It was shown that the supramolecular yield increase with the positive MEP value on the donor site. In order to further explore this relationship between calculated MEP values and supramolecular selectivity three asymmetric ditopic donors containing phenol carboxylic acid and aldoxime groups were screened against a series of asymmetric ditopic acceptors. Nine crystal structures show that the supramolecular outcome can be predicted according to Etter’s rules by ranking donors and acceptors according to calculated MEP values. To explore the possibility of using the same approach with other hydrogen bond donors, three asymmetric ditopic donor ligands containing cyanooxime groups were synthesized and screened against a series of asymmetric ditopic acceptors. Nine out of ten times the supramolecular outcome could be predicted by MEP calculations 1-deazapurine exists in two tautomeric forms (1H and 3H) in aqueous solution, which have very different hydrogen bonding environments. The 3H tautomer forms a self-complementary dimer involving a donor and an acceptor site leaving a second acceptor site vacant. In order to stabilize this tautomer the molecule was screened against a of series hydrogen and halogen bond donors. Four out of five structures obtained showed 3H tautomer. The 1H tautomer is the geometric complement of urea. Therefore the molecule was screened against a series of N,N-diphenylureas and all five structures showed the 1H tautomer.

Chemical warfare agents including organophosphorus nerve agents (NA) continue to be a significant threat to both military and civilian populations. The current Canadian Armed Forces (CAF) treatment of NA poisoning includes administration of the oxime HI-6 (used to reactivate inhibited acetylcholinesterase) in combination with atropine contained in an autoinjector, with a benzodiazepine also being administered. Two salts of HI-6 are currently available: HI-6 2Cl (1-[[[4-(Aminocarbonyl)pyridinio]methoxy]methyl]-2-[(hydroxyiminio)methyl] pyridinium dichloride (MW 376.22 g/mol) and HI-6 DMS (1-[[[4-(Aminocarbonyl)pyridinio]methoxy]methyl]-2-[(hydroxyiminio)methyl] pyridinium dimethanesulfonate (MW 477.49 g/mol). Currently HI-6 is available to the Canadian Armed Forces under a special access program. In order to attain licensure of HI-6 numerous studies must be carried out in animal models to ensure its safety (tolerability and toxicity), efficacy and pharmacokinetics prior to human clinical trials. The present experiment aimed to determine and compare the pharmacokinetic parameters of HI-6 in two animal models under various conditions including: direct comparison of salts (HI-6 2Cl compared to HI-6 DMS), comparison of routes of administration (intramuscular compared to intravenous), comparison of effect of anaesthetic, comparison of different concentrations of HI-6, determination of the effect of atropine sulphate co-administration and evaluation of calculated pharmacokinetic parameters when infusing HI-6. Serial plasma samples were collected and HI-6 levels were quantified using a HPLC method. In all studies a significant difference was reported for absorption/distribution parameters when comparing salts. Additionally the absorption/distribution parameters when comparing routes of administration were significantly different however all other parameters were similar. Significant differences in calculated parameters were reported when examining the effect of anaesthetic on the pharmacokinetics of HI-6. Similar to previous ascending dose studies, differences were reported for the absorption/distribution kinetics. Co-administration of HI-6 with atropine sulphate did not have significant effect on the pharmacokinetics of HI-6. The determined pharmacokinetic values for both salts were accurate for the determination of an infusion rate to reach and maintain a target plasma concentration. Finally the calculated animal model pharmacokinetic data was compared to previously published human clinical trial data and the calculated pharmacokinetic values were found to be similar.

Chemnitz, Techn. Univ., Diss., 2008.

Les dendrimères greffés de L-lysine (DGL) sont des matériaux aux applications potentielles variées (agents antibactériens, antifongiques, ?). Ces dendrimères greffés sont obtenus selon un procédé original mis au point au laboratoire, basé sur la polymérisation des N-carboxyanhydrides (NCA) de Llysine. Le travail effectué au cours de cette thèse a pour objectif d'explorer les différents modes de modification des DGL et d'en évaluer la faisabilité. Pour ce faire, dans une première partie, nous avons détaillé le processus de synthèse et de polymérisation en milieu hétérogène des NCA. Cela nous a permis, ensuite, en modulant la nature de l'agent d'amorçage de la polymérisation des NCA, d'examiner la possibilité d'introduire de nouvelles fonctionnalités (fluorophore, bras de liaison adapté à la ligation) sur la première génération de DGL. Cela a nécessité, en amont, la synthèse d'un bras espaceur hétérobifonctionnel de type polyéthylène glycol. Par la suite, une ligation de type oxime entre les nouveaux DGL de 1ère et de 2e génération et une molécule modèle a été réalisée afin de valider cette approche. Enfin, nous avons pu démontrer que ces dendrimères greffés pouvaient être fonctionnalisés en surface par divers substrats (sucre, guanidine, acide aspartique, acide succinique) leur conférant de nouvelles propriétés et ouvrant ainsi un vaste champ d'application pour ces macromolécules. / L-lysine Dendrigraft (DGL) are materials with various potential applications (antibacterial, antifungal, ...). These dendrigrafts are obtained by an original process, developed in our laboratory, based on the polymerization of N-carboxyanhydrides (NCA) of L-lysine. The work carried out during this thesis was aimed at exploring different methods of modification of DGL and assessing their feasibility. In the first part, we detailed the process of synthesis and polymerization of NCAs in a heterogeneous medium. This allowed us then by modulating the initiator of NCA polymerization to introduce new features (fluorophore, spacer adapted to the ligation) on the first generation of DGL. This required, upstream, the synthesis of a heterobifunctional polyethylene glycol type spacer. Subsequently, an oxime ligation between the new 1st and 2nd generation of DGL and an aldehyde model has been conducted to validate this approach. Finally, we demonstrated that these dendrigrafts could be functionalized on the surface by various substrates (sugar, guanidine, aspartic acid, succinic acid) giving them new properties and opening up a wide scope of applications for these macromolecules.

L'élaboration de squelettes de pipéridinones et lactones a été accomplie de manière très efficace en alliant processus radicalaires et ioniques. La synthèse d'oximes SEM-protégées par un assemblage multicomposant radicalaire permet, après hydrolyse de la fonction oxime, d'obtenir rapidement un aldéhyde fonctionnalisé. Ce composé est ensuite transformé en lactone ou pipéridinone désirée par un processus ionique.Une approche minimisant le nombre d'étapes élémentaires a été développée autorisant ainsi un accès rapide et convenable à une grande diversité de structures. Ces processus peuvent impliquer jusqu'à cinq composants. / The construction of piperidinone and lactone scaffolds has been performed efficiently, combining radical and ionic processes. The synthesis of SEM-protected oximes by a multicomponent radical reaction enables, after hydrolysis of the oxime functional group, the access to a functionalized aldehyde. This compound is then converted into a lactone or a piperidinone by a ionic process.An approach minimizing the number of steps has been developed, thus allowing a rapid and convenient access to a large diversity of structures. These processes may involve up to five components.

Certains pesticides présentent une très bonne activité biologique en serre, lorsqu’ils sont protégés du rayonnement UV, mais pas en champs lorsqu’ils sont exposés à la totalité de la lumière solaire. Une dégradation photochimique par le rayonnement UV est alors suspectée. C’est le cas de la famille de fongicides contenant un groupement oxime dont nous avons étudié en détail la photodégradation d’un point de vue expérimental et théorique. La cinétique de phototransformation de ces fongicides a été mesurée en solution et en phase solide et les photoproduits de réaction ont été identifiés et quantifiés. L’ensemble des résultats nous a alors permis de proposer un mécanisme de photodégradation. Ces fongicides subissent à la fois une photoisomérisation et une photodégradation par rupture homolytique de la liaison oxime. Le rôle de certains éléments structuraux dans ces transformations a pu être établi grâce à plusieurs analogues. Une étude de modélisation moléculaire menée en parallèle a permis de déterminer la nature des voies réactionnelles mises en jeu après l’excitation de la molécule et ainsi d’expliquer les observations expérimentales. Ce travail avait pour objectif d’améliorer la photostabilité de cette famille de fongicides par des modifications structurales tout en respectant l’activité biologique par ailleurs tout à fait remarquable de ces composés. Le remplacement de l’oxime par un oxétane préparé par une réaction de Paternò-Büchi a été envisagé. / Some pesticides present a great biological activity in green house, while they are protected from UV radiations, but not in the field, while they are exposed to the whole spectrum of solar light. A photochemical degradation by UV light is then suspected. That is the case of the group of fungicides which contain an oxim moiety and that we studied the photodegradation in detail, both from experimental and theoretical points of view. The kinetics of phototransformation of these fungicides have been mesured in solution and in the solid phase and photoproducts have been identified and quantified. These results allowed us to propose a mecanism of photodegradation. These fungicides undergo simultanously a photoisomerisation and a photodegradation by a homolytic cleavage of the oxim bond. The role of some structural elements in these transformations has been set up thanks to several analogues. A parallel study of molecular modelisation allowed the determination of the nature of reactive paths followed after the excitation of the molecule and therefore the explanation of experimental observations. The objective of this work was to improve the photostability of this group of fungicides by structural modifications while keeping the remarquable biological activity of these compounds. The replacement of the oxim moiety by an oxetane prepared by a Paternò-Büchi reaction has been considered.

Pyrrolo[1,2-a]pyrazine is one of the isomers of pyrolodiazine family. Pyrrolo[1,2-a]pyrazine possesses a bicyclic heteroaromatic structure that have 10 electrons. It has various biological importances in synthetic chemistry / therefore, many different approaches to generate this skeleton have been developed so far. In this study, our prior aim was to develop a new synthetic methodology for the formation of pyrrolo[1,2-a]pyrazine moiety. In the first part of this focus, the starting compound, methyl 2-(2-methoxy-2-oxoethyl)-1-(prop-2-yn-1-yl)-1H-pyrrole-3-carboxylate was successfully synthesized, then the conversion of the ester group at the lower arm to the amine group was carried out. Heteroatom cyclization catalyzed by CuI afforded the desired substituted pyrrolo[1,2-a]pyrazine structure. In the second part, it was aimed to synthesize new compounds with unusual structures which are not described in the literature / namely, as pyrrolo[1,2-a]pyrazine N-oxide. In this direction, first pyrrole was submitted to Vilsmeier-Haack reaction to attach a formyl group at C-2. Substitution reaction then effectively gave 1-(prop-2-yn-1-yl)-1H-pyrrole-2-carbaldehyde, which was a key molecule to synthesize the aldoxime. AuCl3 catalyzed cyclization of the corresponding oxime afforded pyrrolo[1,2-a]pyrazine N-oxide. In the next step, Sonogashira coupling reactions were carried out to obtain terminal alkynes (RC&equiv / CR&#039 / ) starting from 1-(prop-2-yn-1-yl)-1H-pyrrole-2-carbaldehyde. The aim of this part was to study the effect of aryl groups to the activated alkyl functional group by a metal catalyst. In this case, unexpected oxime-oxime transformation was observed, which is unprecedented in the literature

Les neurotoxiques organophosphorés (NOPs) sont des inhibiteurs irréversibles de l’acétylcholinestérase, une enzyme jouant un rôle clé dans la transmission de l’influx nerveux. Une intoxication par ces substances provoque de graves symptômes pouvant aboutir au décès des sujets empoisonnés. Bien qu’interdits par une convention internationale ratifiée par 190 pays, le contexte géopolitique actuel ravive la hantise d’une menace chimique contre des populations civiles, renouvelant l’intérêt de développer de nouveaux remèdes contre une intoxication aux NOP. A l’heure actuelle, les antidotes utilisés contre ces intoxications sont les mono- et bis- pyridinium aldoximes portant une ou deux charge(s) positive(s) permanente(s), qui présentent de nombreuses limitations, dont leur très faible capacité à traverser la barrière hémato-encéphalique et à réactiver efficacement les AChEs inhibées par les NOP dans le système nerveux central (SNC). Par ailleurs, leur efficacité est très dépendante de la nature du NOP utilisé, et il n’existe pas, aujourd’hui, de réactivateur universel. Dans ce contexte, le développement de nouveaux réactivateurs efficaces est un réel défi. Au cours de cette thèse, l’optimisation de la synthèse de cinq réactivateurs non chargés incorporant une amine cyclique en tant que ligand du site périphérique et la 3-hydroxypyridine aldoxime en tant que fonction réactivatrice a été développée pour évaluation in vivo. Dans cette continuité, vingt-et-un réactivateurs non chargés inédits comportant un ligand aminé du site périphérique de l’enzyme associée à la même fonction réactivatrice 3-hydroxypyridine aldoxime ont été conçus, synthétisés et testés sur l’AChE humaine inhibée par différents NOPs mais aussi sur les récepteurs nicotiniques. Certains d’entre eux ont été testés in vivo sur la souris. Parmi les réactivateurs synthétisés, certains possèdent des efficacités de réactivation identiques, voire meilleures que les oximes de référence utilisées de nos jours tout en ayant un effet antagoniste des récepteurs nicotiniques ouvrant ainsi la voie aux réactivateurs dits « Multi-cibles ». Avec comme objectif de traverser la barrière hémato-encéphalique en utilisant les transporteurs GLUTs présents sur les cellules endothéliales constituant cette barrière, quatre réactivateurs incorporant un motif carbohydrate ont été resynthétisés et évalués in vivo et in vitro. Enfin, de nouvelles fonctions réactivatrices constituées d’un motif thiadiazole-aldoxime et naphtaldoxime ont été étudiées ouvrant la voie à de nouvelles familles de réactivateurs et, pour la dernière fonction, remettant en cause le cahier des charges utilisé jusqu’alors pour la conception de nouveaux réactivateurs. / Organophosphorus nerve agents (OPNA) are irreversibly acetylcholinesterase (AChE) inhibitors, a key enzyme in the central nervos system playing a pivotal role in neurotransmission. OPNA poisoning induces to serious symptoms that can lead to death by respiratory failure. Despite an international convention prohibiting the use of chemical weapons, the current geopolitical context is reviving the fear of a chemical threat against civilian populations, and has renewed the interest of developing new remedies for OPNA poisoning. Nowadays, medical countermeasure used against OPNA intoxications are based on mono- and bis-pyridinium aldoximes carrying one or two permanent positive charge(s), which present many limitations, including their very low capacity to cross the blood-brain barrier and to reactivate effectively ChEs nhibited by NOPs in the central nervous system (CNS). Moreover, their effectiveness is highly dependent on the nature of the NOP used, therefore, there is no universal reactivator. In this context, the development of new effective reactivators is a real challenge. In this PhD, an optimized synthetic access to five uncharged reactivators incorporating a cyclic amine as peripheral site ligand and 3-hydroxypyridine aldoxime as reactivating function was developed for in vivo evaluation. Following up on this, twenty-one new uncharged reactivators bearing unprecedented cyclic amines as peripheral site ligand associated with our reactivating function were designed, synthetized and evaluated for reactivation on human AChE inhibited by several NOPs but also in vivo on mice and as antagonists on nicotinic receptors in vitro. Among these reactivators, some have identical or better reactivation efficiencies than the reference oximes used today while having a nicotinic receptor antagonist effect ; thus, paving the way for « Multi-target » reactivators. Aiming at an active BBB crossing using the GLUTs receptors, four reactivators including a carbohydrate moiety have been resynthetized and biologically evaluated. Last but not least, new reactivator functions consisting of a thiadazole-aldoxime and naphtaldoxime moieties have been studied, paving the way to new families of uncharged reactivators and, especially for the last function, calling into question design specifications of new reactivators.

Malaria continues to cause significant mortality in sub-Saharan Africa and elsewhere, and existing vector control measures are being threatened by growing resistance to pyrethroid insecticides. With the goal of developing new human-safe, resistance-breaking insecticides we have explored several classes of acetylcholinesterase inhibitors. In vitro assay studies demonstrate that tri- and difluoromethyl ketones can potentially inhibit An. gambiae AChE (AgAChE). These compounds inhibit the enzyme by making a covalent adduct with the catalytic serine of AChE. Trifluoromethyl ketones however are poor inhibitors of the G119S resistant mutant of AgAChE. However difluoromethyl ketones can inhibit G119S AgAChE and compound 3-10g showed an IC₅₀ value of 25.1 nM after 23h incubation time. Despite this potent inhibition of AgAChE, the tri-, di-, and (mono)fluoroketones showed very low toxicity to An. gambiae, perhaps due to hydration and rapid clearance. In an attempt to improve An. gambiae toxicity, oximes and oxime ethers of these compounds were prepared as potential prodrugs. These structures identified trifluoromethyl ketone oxime 3-2d as a potent toxin against both wild-type (G3-strain) and a multiply resistant (Akron) strain of An. gambiae. This compound is within 3-fold of the toxicity of propoxur to wild type An. gambiae (LC₅₀ values of 106 and 39 µg/mL, respectively). Most significantly, 3-2d was much more toxic than propoxur to multiply-resistant (Akron) strain An. gambiae (LC₅₀ = 112 and >5,000 µg/mL, respectively). However, thus far we have not been able to link the toxicity of these compounds to a cholinergic mechanism. Pre-incubation studies suggest that significant hydrolysis of these compounds to TFKs does not occur over 22 h at pH 7.7 or 5.5. The mechanism of action of 3-2d remains unknown. Our enzyme inhibition studies have demonstrated that 3-2d does not hydrolyze to the trifluoromethyl ketone 2-9d at pH 7.7. The high Akron toxicity of 3-2d and poor inhibition of G119S AgAChE by 2-9d argue against enzyme mediated conversion of 3-2d to 2-9d within the mosquito. Thus, we can rule out an AChE inhibition mechanism for toxicity. Additional experiments by our collaborator (Dr. Jeffrey Bloomquist, University of Florida) also rule out inhibition of mitochondrial respiration or agonism of the muscarinic acetylcholine receptor. Future work will address other potential insecticidal modes of action. / Ph. D.