The synthesis of heterocycles using radical intermediates has become an important area of research in recent years. The aim of our research was to develop radical methodologies to construct heterocycles on solid-support. Tri-cyclic benzimidazole derivatives are desirable synthetic targets with a range of biological activity and are part of certain anti-tumour agents. Solid-supported radical reactions with substituted benzimidazoles were performed under different experimental conditions, including different solvents, three different resins (Wang, Merrifield and Rink) and different radical reagents. 4-Mercaptobenzoic acid moiety served as a traceless linker in radical ipso-substitution reactions of benzimidazole precursors attached to solid-support to construct tri-cyclic and tetracyclic benzimidazole adducts. The solution-phase radical ipso-substitution protocol was quite successfully translated onto solid-support.

The effect of hydrogen bonding on the conformation of organic moleculesunifies two projects in this thesis. In one project, the stability of the intramolecularhydrogen bond in derivatives of 2-guanidinobenzimidazole was studied bydynamic 1H NMR spectrometry. The impact that this intramolecular hydrogenbond had on the bond order of the neutral guanidino group and on the dynamicconformation of these aromatic structures was related to the concept of hydrogenbond-assisted resonance. In another project, an oligomer possessing repetitiveconformation and capable of much inter- and intramolecular hydrogen bondingwas designed and synthesized. The sensitivity of this oligomer to changes inanion concentration, as well as its own propensity to self-aggregate weremeasured.Hydrogen bonds found in many biological oligomers are connected thougha system of conjugated bonds. Guanidinobenzimidazole is a conjugated systemof carbon and nitrogen, connected by an intramolecular hydrogen bond. Severalderivatives of guanidinobenzimidazole were synthesized, and the effect ofseveral simple alkyl for hydrogen substitutions were studied.Guanidinobenzimidazole was used as a model to study what effect theconjugation and the intramolecular hydrogen bond have on each other.The formation of redundant low energy hydrogen bonds is universal inbiological oligomers. In DNA and RNA multiple hydrogen bonds are formed witha typical energy contribution of only 1-2 kcal/mol. Individually, these interactionsdo not give the biological oligomers their conformational stability, but togetherthey are very stable. The urea and amide based oligomers designed in the workand discussed in the thesis should form multiple hydrogen bonds withthemselves and/or with anionic guests. Chiral oligoureas were designed topossess this characteristic of cooperative conformation that so many biologicaloligomers and polymers share.

The present investigation yielded an orange product upon refluxing 2-butyramido-3-chloro-1,4-naphthoquinone and 2-aminopyridine in ethanol. When this material was purified, by recrystallization from glacial acetic acid, the melting point was 306 [degrees]. This compound has been shown to be benzo(d)pyrido(a)-benzimidazole-5,12-quinone by the present investigation.

A conjugated bis-benzimidazole chromophore is predicted to show absorptions in the near-infrared (NIR) region of the electromagnetic spectrum. However, there are no reports to-date of any NIR absorbing and emitting dyes that are based on a bis-benzimidazole structural backbone. This thesis reports recent advancements in the discovery and study of this new class of dyes. Following literature procedures, the syntheses of bis(benzimidazolyl)methane compounds are successful. An unexpected product isolated during the attempted oxidation of a bis(benzimidazolyl)methane compound using p-chloranil showed intense absorption in the NIR (λmax = 712 nm, ε = 14600 L·mol-1·cm-1), solubilities in polar solvents like methanol and water, and electrochemical activities. X-ray crystallography, mass spectrometry, and NMR spectroscopy confirmed the connectivity and structure of the product to contain a combination of quinone and benzimidazole moieties, which later revealed to be the core chromophore by computational studies. This unprecedented combination of moieties gave a chromophore that is predicted to absorb in the far-red even without substitution. Attempts to synthesize boron-based bis-imidazole dyes with N-methylation shed light on the feasibility of the design of such moiety. Considering the additional functionality that could be accessed through the methylation of the labile benzimidazole nitrogen atoms, N-methylated bis(benzimidazolyl)methane precursors were successfully synthesized and fully characterized. Attempts of the boron coordination showed promising signs, as the 1H, 11B, and 19F NMR spectra showed solid evidence of the successful isolation of the boron chelate. Computational studies of methyl, phenyl, and triazole-substituted boron chelate derivatives projected absorptions in the NIR region. Intense transitions are found to be based on frontier molecular orbitals and differ significantly among the derivatives, predicting substantial tunability of this type of dyes. / Graduate / 2022-02-18

Microbe resistence is a serious issue, especially as they have become resistant to most well known drugs. Therefore this is considered as a global problem and is now dealt with at a poitical level. Since no new classes of antimicrobial agents have been discovered in the past three deacdes, the development of new drugs is extremely urgent. Therefore the aim of this project was to synthesise derivatives of benzimidazole, and then assesses their antimicrobial activities in vitro by using disc (well) diffusion and MICs tests. A total of 69 benzimidazole derivatives, with substituents at positions 1, 2, and 5, were synthesised, characterised and tested against selected bacteria and fungi. In addition, six bezimidazole silver complexes were prepared and evaluated for their antimicrobial behavior. The SAR showed that the antimicrobial activity of the compounds depended on the substituents attached to the bicyclic heterocycle. Some promising results were obtained. In particular, 5 compounds displayed antibacterial activity against two MRSA strains with MIC values corresponding to ciprofloxacin, which can be considered significant. The compounds have some common features; four possess 5-chloro or 5-bromo substituents; two are derivatives of (S)-2- ethanaminebenzimidazole and the others are derivative of one 2-(chloromethyl)-1Hbenzo[d]imidazole, (1H-benzo[d]imidazol-2-yl)methanethiol and 2-(methoxymethyl)-1-methyl-1H-benzo[d]imidazole. The results from the antifungal screening were very interesting as there were 26 compounds, including two silver complexes, which were potent fungicides against the selected fungal species. They showed equivalent or greater potentency in their MIC values than amphotericin B. In particular, the 5-fluoro, 5-chloro and 5-bromo benzimidazole showed broad spectrum activity. / Saudi Culture Bureau and King Saud University

No description available.

Le cancer, principale cause de mortalité dans le monde, est un problème majeur de santé publique. Malgré les nombreux traitements disponibles, il est nécessaire de développer de nouvelles thérapies plus efficaces et moins envahissantes. Aujourd’hui la connaissance du génome humain a dirigé la recherche vers de nouvelles approches: il est possible de moduler la réponse biologique en contrôlant l'accès aux informations génétiques via la régulation épigénétique.L’épigénétique est l’ensemble des modifications de l’expression des gènes n’entraînant pas de modifications dans la séquence d’ADN, qui mènent à un phénotype héritable et stable. Chez les eucaryotes, la régulation épigénétique implique des modifications covalentes de l'ADN (méthylation) et des histones (acétylation, méthylation…). Ces phénomènes modifient la structure de la chromatine, aboutissant à une configuration "ouverte" ou "fermée" permettant la transcription ou la répression de gènes. Dans une situation cancéreuse, le profil épigénétique est modifié ; la méthylation anormale de l’ADN ou des histones mène à la répression de certains gènes comme des gènes suppresseurs de tumeur, ou à l’expression des oncogènes. Contrairement aux changements génétiques irréversibles, les aberrations épigénétiques sont des modifications chimiques réversibles. Ainsi, des molécules capables de rétablir l'équilibre épigénétique représentent des outils thérapeutiques potentiels contre le cancer.La méthylation et l’acétylation sont les modifications épigénétiques les plus étudiées. La méthylation de l’ADN est catalysée par les ADN méthyltransférases (DNMTs), et la méthylation des histones par les histones méthyltransférases (HMTs).Le sujet de ce projet doctoral est porté sur les HMTs et en particulier sur DOT1L (DOT1 like, disruptor of telomericsilencing), responsable des méthylations du résidu Lys79 de l’histone 3 (H3K79), conduisant à la transcription des oncogènes. En effet, des études ont montré que DOT1L est liée à la leucémie et se révèle être une cible intéressante à inhiber. DOT1L comme les DNMT ont un même cofacteur : le SAM (S-adénosyl-L-méthionine). Certains de leurs inhibiteurs présentent un mécanisme d'inhibition commun : ils entrent en compétition avec SAM.Nous présentons la conception basée sur des études de modélisation moléculaire, et la synthèse multi-étapes des séries des molécules formées par 3 motifs principaux : a) un motif aminopyrimidine, b) un motif de type benzimidazole ou phénylurée, liés par c) un groupement phényle ou hétérocyclique. L’activité des composés synthétisés sur DOT1L a été évaluée et des relations structure-activité (RSA) ont été établies. L’activité sur DNMT et d’autres HMTs a été déterminée également afin d’étudier la spécificité de nos composés.Différents structures ont été identifiées comme point de départ pour aboutir à des inhibiteurs sélectives de DOT1L ou à des inhibiteurs mixtes DOT1L/DNMT. Ces molécules sont considérées comme des outils thérapeutiques intéressants dans le traitement du cancer. / Cancer is a serious issue of public health as it is one of the main causes of mortality worldwide. Despite the multiple available treatments, it is necessary to develop more efficient and less invasive therapies against cancer. The knowledge of the human genome and epigenome has directed research to new cancer treatment approaches: it is possible to modulate the biological outcome by controlling the access to the genetic information by means of the epigenetic regulation.Epigenetics are the changes happening on the genome without modifying its DNA sequence, leading to a heritable andstable phenotype. In the eukaryotic chromatin, epigenetic regulation implies covalent modifications of DNA and histones. These chemical modifications remodel the chromatin structure leading to an “opened” or “closed” configuration, which is related to the expression or repression of genes. The epigenetic landscape is altered in cancers; for example, abnormal methylation leads to the silencing of certain genes (such as tumor suppressor genes), or to the over-expression of oncogenes. Unlike genetic alterations that are irreversible, epigenetic aberrations are reversible. Thus, molecules that can reestablish the epigenetic balance represent potent therapeutic tools for cancer treatment.Methylation and acetylation are the most studied epigenetic modifications. DNA methylation is carried out by the DNAmethyltransferases (DNMTs) and histone methylation by the histone methyltransferases (HMTs).This PhD project was focused on the histone methyltransferase DOT1L (DOT1 like, disruptor of telomeric silencing), responsible of methylation of residue Lys79 of histone 3 (H3K79), which leads to the transcription of some oncogenes. Recent studies have shown that DOT1L is implicated in MLL-rearranged leukemia (MLL-r, Myeloid-Lymphoid Leukemia) thus it is a potent target in cancer. As DOT1L and DNMTs share the same cofactor, S-adenosyl-L-methionine (SAM), DNMT and DOT1L inhibitors can present a common inhibition mechanism by competing with SAM.We present herein the in silico – based design, and the multi-step synthesis of some series of molecules containing 3 main moieties: a) an aminopyrimidine motif and b) a benzimidazole or phenylurea motif, linked by c) a phenyl or heterocycle motif. DOT1L activity was determined for the different compounds synthesized and structure-activity relationships (SAR) were established. The activity on DNMT and other HMTs was determined as well, in other to study the DOT1L specificity of our compounds.Different scaffolds were identified to obtain DOT1L-selective or DOT1L/DNMT dual inhibitors. These molecules are interesting therapeutic tools for cancer treatment.

Ce travail de thèse s'inscrit dans la continuité des travaux de recherche sur l'utilisation d'hétérocycles azotés pour l'élaboration de membranes échangeuses de protons pour piles à combustible de type PEMFC fonctionnant sous faible taux d'humidité relative (HR < 25 %) et à des températures allant jusqu'à 200 °C pour l'application automobile. Pour cela, trois nouveaux copolymères partiellement fluorés porteurs de trois groupements azole (imidazole, benzimidazole et 1H-1,2,4-triazole) ont été synthétisés et caractérisés. Ils ont ensuite été utilisés pour l'élaboration de membranes polymères (20 µm < épaisseurs < 100 µm) par mélange avec le s-PEEK. Ces membranes sont stables thermiquement jusqu'à 210 °C. Les trois séries de membranes ont été comparées et les meilleurs résultats de conductivité protonique ont été obtenus pour celles contenant le 1H-1,2,4-triazole (σ = 7,0 mS.cm-1, 140 °C, HR < 25 %). Les propriétés mécaniques de ces membranes ont été mesurées et ont montré des valeurs comparables à celles des principales membranes commerciales (de type Nafion®). Afin d'obtenir une meilleure structuration de ces membranes, une stratégie d'élaboration de pseudo réseaux semi-interpénétrés de s-PEEK dans un réseau polymère réticulé a été mise au point. Pour cela, de nouveaux terpolymères porteurs de groupements 1H-1,2,4-triazole et de groupements cyclocarbonate réticulables par la réaction cyclocarbonate / amine ont été synthétisés et caractérisés. Ces terpolymères ont été mélangés à du s-PEEK puis réticulés par une diamine pour former des pseudo réseaux semi-interpénétrés de faibles épaisseurs (20 µm < e < 60 µm) qui ont été caractérisés. Ces membranes à architecture pseudo réseaux semi-interpénétrés ont montré de meilleures propriétés mécaniques mais des valeurs de conductivité protonique légèrement inférieures à celles des membranes non réticulées. Enfin, les membranes réticulées ou non ont été dopées par l'acide phosphorique pour augmenter leurs valeurs de conductivité protonique. Des essais en mono-cellule de PAC de ces membranes dopées ont été effectués et ont montré de bonnes performances. Des estimations par extrapolations des résultats ont ensuite été effectuées à plus hautes températures (140 – 200 °C) et ont montré que les valeurs de conductivité protonique atteignent jusqu'à 210 et 250 mS.cm-1, à 180 et 200 °C, HR < 25 % (valeurs extrapolées). Ces valeurs extrapolées doivent être vérifiées par la réalisation de mesures de conductivité protonique à ces températures (140 – 200 °C). / This work concerns the syntheses and characterizations of new proton exchange polymer membranes containing N-heterocyclic compounds for PEMFC working under low relative humidity (HR < 25 %) and temperatures up to 200 °C for automotive applications. Three new partially fluorinated copolymers bearing different azole compounds (imidazole, benzimidazole or 1H-1,2,4-triazole) as pendant groups have been synthesized and characterized. Then, they have been used to synthesize blend polymer membranes with s-PEEK (20 µm < thickness < 100 µm) that showed thermal stabilities up to 210 °C. These new families of membranes have been compared and highest proton conductivity values have been observed for 1H-1,2,4-triazole containing membranes (σ = 7,0 mS.cm-1, 140 °C, HR < 25 %). Mechanical properties and oxidative stability of these membranes have been assessed and showed similar values than main commercially available membranes. To improve membranes structuration, pseudo semi-interpenetrating polymer networks have been synthesized. Thus, original cross-linkable terpolymers bearing 1H-1,2,4-triazole and cyclocabonate functions as pendant groups have been synthesized and blended with s-PEEK as linear polymer to synthesize new polymers membranes (20 µm < thickness < 60 µm). Cross-linking has been carried from the cyclocarbonate/diamine reaction to get pseudo semi-interpenetrated polymer networks. Finally, both pseudo semi-interpenetrated polymer networks and uncross-linked membranes were doped by immersion in phosphoric acid solution to increase proton conductivity of these materials. Single cell fuel cell tests have been carried out and showed good performances. High temperatures (140 – 180 °C) proton conductivity values of these doped membranes have been estimated from extrapolation curves and reached up to 210 and 250 mS.cm-1, at 180 and 200 °C, HR < 25 %, respectively (extrapolated values). Proton conductivity values should be assessed at these targeted temperatures (140 to 200 °C).

In order to study their electrochemical and optical properties, two donor-acceptordonor (D-A-D) type monomers / 4&#039 / -(tert-butyl)-4,7-bis(4-hexylthiophen-2- yl)spiro[benzo[d]imidazole-2,1&#039 / -cyclohexane] (BIHT) and 4&#039 / -(tert-butyl)-4,7-bis(2,3- dihydrothieno[3,4-b][1,4]dioxin-5-yl)spiro[benzo[d]imidazole-2,1&#039 / -cyclohexane] (BIED), were electrochemically polymerized. These properties were investigated by cyclic voltammetry and UV&ndash / Vis-NIR Spectroscopy techniques. Effects of different donor groups / 3-hexylthiophene and 3, 4-ethylenedioxythiophene (EDOT), on new benzimidazole group, 4&#039 / -(tert-butyl)spiro[benzo[d]imidazole-2,1&#039 / -cyclohexane], were investigated. These pendant groups cause slight differences in optical band gaps, which are 1.19 eV for PBIHT, 1.15eV for PBIED. PBIHT and PBIED have both nand p- doping. Both of them have broad absorption in the visible region. In NIR region, both polymers revealed 46 % transmittance with high switching times. PBIED and PBIHT showed multichromic properties. PBIED is green at neutral state. For the most oxidized and reduced states, it is blue and red, respectively. PBIHT is blue at neutral state, transmissive-gray in oxidized state and transmissive greenishgray in reduced state.

In this study / ferrocenyl and naphthalenyl substituted quinoxaline derivatives / 5,8- bis (2,3- dihydrothieno [3,4-b] [1,4] dioxin-5-yl)-2- (naphthalen-2-yl)- 3- ferrocenyl- 4a,8a-dihydroquinoxaline / 5,8- bis (2,3-dihydrothieno [3,4-b] [1,4]dioxin-5-yl) -2- (phenyl) -3-ferrocenylquinoxaline / 5,8-bis (2,3-dihydrothieno [3,4-b] [1,4]dioxin-5-yl) -2,3- di(naphthalen-2-yl)quinoxaline and trihexylthiophene and thiophene coupled benzimidazole derivatives / 4-(tert-butyl)-4,7-bis(4-hexylthiophen-2-yl)spiro[benzo[d]imidazole-2,1-cyclohexane] and 4-(tert-butyl)-4, 7-bis(thiophenyl)spiro[benzo[d]imidazole-2,1-cyclohexane] were used as photosensitizers to broaden the active area of diaryliodonium salts. Both quinoxaline and benzimidazole derivatives are expected to be efficient in cationic photopolymerization with a variety of vinyl and oxide monomers at room temperature upon long wavelength UV irradiation. Photopolymerization will be initiated by diphenyliodonium salts and monitored with Optical Pyrometry. Characterization will be completed with optical absorption, flourescence studies and photopolymerization under solar irradiation.