La kératite à Acanthamoeba (KA) est une kératite infectieuse rare et grave,potentiellement cécitante. L'infection est causée par Acanthamoeba spp., unprotozoaire ubiquitaire présent dans le sol, l'air et l'eau. Jusqu'à 85% des cas de KAsont associés au port de lentilles cornéennes, et plus rarement suite à untraumatisme.Actuellement, aucune molécule n’a d’autorisation de mise sur le marché danscette indication dans l'Union européenne et aux États-Unis. Ces dernières années,des combinaisons d'agents anti-amibiens tels que les biguanides et les diamidinesont été utilisées comme traitement de référence. Cependant, les schémasthérapeutiques et les concentrations d'agents actifs reposent sur des donnéesempiriques. Récemment, le voriconazole, antifongique triazolé, a été utilisé avecsuccès pour traiter des KA humaines. Malgré cela, la communauté ophtalmologiquese heurte le plus souvent dans les formes sévères à de grandes difficultés de prise encharge et se retrouve parfois en situation d’impasse thérapeutique. La pertefonctionnelle et anatomique de l’oeil est encore possible.A partir d’un modèle de KA chez le rat, plusieurs molécules et voiesd’administration ont été testées. Dans une première partie, en lien avec projeteuropéen ODAK (Orphan drug for Acanthamoeba Keratitis), nos travaux ont suggéréqu’une concentration de collyre PHMB supérieure ou égale à 0,04% devait êtrepréférée. Dans une deuxième partie, nous avons pu montrer la supériorité duvoriconazole en collyre par rapport à la voie orale. Enfin, l’étude de lapharmacocinétique du voriconazole et du posaconazole après injections directesintracornéennes, démontre leur faible utilité en clinique humaine du fait de lafréquence nécessaire de réinjection, bien que des analyses complémentairesconcernant le posaconazole en collyre pour confirmer son intérêt soient nécessaires.L'ensemble de ces travaux pourrait permettre d’adapter les protocolesthérapeutiques de la KA. / Acanthamoeba keratitis (AK) is a rare and severe form of infectious keratitis,which is potentially sight-threatening. The infection is caused by Acanthamoeba spp.a common protozoan present in soil, air and water. Up to 85% of AK cases areassociated with contact lens wearing, more rarely after corneal injury.Currently, there are no agents approved for the treatment of AK in theEuropean Union or in the United States of America. In recent years, combinations ofunlicensed anti-amoebic agents such as biguanides and diamidines have been usedas the reference treatment. Treatment regimens and concentrations of active agentsare based on empirical data. Recently, voriconazole, a mono-triazole, wassuccessfully used to treat cases of human AK. Despite this, the ophthalmologicalcommunity is most often faced with severe forms of the disease with severemanagement difficulties and sometimes with a situation of therapeutic impasse. Thefunctional and anatomical loss of an eye can occur.Several agents and routes of administration have been tested in a rat model ofAK. First, as part of the European ODAK project (Orphan drug for AcanthamoebaKeratitis), our work suggested that a concentration of PHMB eye drops greater thanor equal to 0.04% should be preferred. Second, we were able to show the superiorityof voriconazole in eye drops compared to the oral route. Finally, our study on thepharmacokinetics of voriconazole and posaconazole after intrastromal injections,demonstrates their low utility in human because of the need for frequent reinjection.Nevertheless, additional analyses are necessary to confirm the interest ofposaconazole eye drops. All of this work could make it possible to adapt thetherapeutic protocols of AK.

[pt] A importância terapêutica dos compostos contendo 1,2,3-triazóis deve-se ao seu espectro de atuação farmacológica, entre as quais podemos destacar a ação anticâncer, antiviral, antibacteriana, antifúngica, anticonvulsivante entre outras. A facilidade sintética de obtenção de 1,2,3- triazóis por meio da reação de cicloadição 1,3 –dipolar catalisada por cobre (CuAAc), também denominada click chemistry, bem como a reação de cicloadição térmica 1,3-dipolar, torna este grupo bastante atraente como um grupo farmacofórico. O presente trabalho tem como objetivo geral o planejamento, síntese e avaliação de fenil(1-fenil-1H-1,2,3-triazóis-4-il)metanol, também denominados hidróxi-1,2,3-triazóis, visando analisar suas ações farmacológicas frente a leishmaniose. Duas estratégias foram desenvolvidas para a obtenção destes compostos: (i) reação de cicloadição 1,3-dipolar catalisada por cobre (CuAAC) entre 1-fenil-3-(trimetilsilil)prop-2-in-1-óis e aril azidas substituídas previamente preparadas levando assim a obtenção dos fenil(1-fenil-1H-1,2,3-triazóis-4-il)metanol com rendimentos entre 20 e 30 por cento. As aril azidas foram preparadas à partir das anilinas em 60 a 85 por cento de rendimentos e os 1-fenil-3-(trimetilsilil)prop-2-in-1-óis foram preparados à partir da adição de etiniltrimetilsilano aos benzaldeídos comerciais (ii) reação de cicloadição térmica entre aril azidas e (E)-3-(dimetilamino)-1-fenilprop-2-en-1-ona - previamente preparadas à partir de 4-bromoacetofenonas, em rendimentos de 40-50 por cento, seguida de redução dos fenil(1-fenil-1H-1,2,3-triazóis-4-il)metanona com rendimentos variando entre 35-50 por cento levando assim a obtenção dos fenil(1-fenil-1H-1,2,3-triazóis-4-il)metanóis com rendimentos entre 20 e 30 por cento. Os compostos sintetizados foram caracterizados por técnicas de espectroscopia de ressonância magnética nuclear (RMN), infravermelho (IV) e espectrometria de massas (CG-MS). / [en] The therapeutic importance of compounds containing 1,2,3-triazoles is due to their spectrum of pharmacological activity, among which we can highlight the anticancer, antiviral, antibacterial, antifungal, anticonvulsant action, among others. The synthetic facility to obtain 1,2,3-triazoles through the 1,3-dipolar copper-catalyzed cycloaddition reaction (CuAAc), also called click chemistry, as well as the 1,3-dipolar thermal cycloaddition reaction, makes this group quite attractive as a pharmacophoric group. The present work has a general objective the planning, synthesis and evaluation of phenyl (1-phenyl-1H-1,2,3-triazoles-4-yl) methanol, also called hydroxy-1,2,3-triazoles, aiming to analyze their pharmacological actions against leishmaniasis. Two strategies were developed to obtain these compounds: (i) 1,3-dipolar copper-catalyzed cycloaddition reaction (CuAAC) between 1-phenyl-3- (trimethylsilyl) prop-2-in-1-ois and aryl azides substituted previously prepared thus leading to obtaining phenyl (1-phenyl-1H-1,2,3-triazoles-4-yl) methanol with yields between 20 and 30 percent. Aryl azides (50a-i) were prepared from anilines in 60 to 85 percent yields and 1-phenyl-3- (trimethylsilyl) prop-2-in-1-ois were prepared from the addition of ethinyltrimethylsilane to commercial benzaldehydes (ii) thermal cycloaddition reaction between aryl azides and (E) -3- (dimethylamino) -1-phenylprop- 2-en-1-one - previously prepared from 4-bromoacetophenones, in yields of 40-50 percent, followed by reduction of phenyl (1-phenyl-1H-1,2,3-triazoles-4- il) methanone with yields varying between 35-50 percent thus leading to the obtaining of phenyl (1-phenyl-1H-1,2,3-triazoles-4-yl) methanols with yields between 20 and 30 percent. The synthesized compounds were characterized by nuclear magnetic resonance (NMR), infrared (IR) and mass spectrometry (CG-MS) techniques.

Les analogues de nucléosides sont d'une importance considérable dans la recherche de nouveaux candidats médicaments antiviraux et anticancéreux. La ribavirine est en effet le premier nucléoside triazole antiviral synthétique. Elle est toujours activement utilisée en milieu hospitalier pour le traitement de l'hépatite C et celui des pandémies virales émergentes. Récemment, le besoin de nouveaux agents thérapeutiques efficaces dotés de nouveaux mécanismes d'action a donc créé un regain d'intérêt dans la création de nouvelles entités structurelles de nucléosides triazoles. Au cours de mon doctorat, j’ai été activement engagée dans l’élaboration de nouvelles structures O-arylées et S-arylées de nucléosides triazoles. Les nucléosides triazoles O-arylés ont été obtenus par substitution nucléophile aromatique initiée par micro-ondes, tandis que les nucléosides triazoles S-arylés ont été synthétisés par réaction de couplage C-S en utilisant un catalyseur palladié possédant des ligands mixtes nouvellement mis au point dans notre laboratoire. Le concept du système de catalyseur à ligands mixtes est extrêmement avantageux et enrichissant puisqu’il permet de combiner de façon rationnelle des ligands possédant des fonctionnalités complémentaires afin de promouvoir des réactions avec des substrats pour lesquels ces réactions sont très compliquées. Enfin, afin d'améliorer la solubilité dans l'eau des analogues nucléosidiques triazoles actifs que nous avons identifiés, j’ai tenté de conjuguer le nucléoside triazole à un dendrimère amphiphile dans le but d'élaborer un système de délivrance efficace des médicaments et ainsi d’améliorer leur biodisponibilité. / Nucleoside mimics are of considerable importance in the search of antiviral and anticancer drug candidates. One noteworthy example is ribavirin, the first synthetic antiviral triazole nucleoside discovered 40 years ago, which is still actively in clinic use for treating hepatitis C infection and emerging viral pandemics. Recently, ribavirin has been also reported to demonstrate apoptosis-related anticancer effects and is in clinical trial for treating leukemia. Consequently, there is a renewed interest in creating new structural entities of triazole nucleosides with the aim of developing potent therapeutic agents with novel mechanisms of action. During my PhD program, I have been actively engaged in constructing structurally novel O-arylated and S-arylated triazole nucleosides. The O-arylated triazole nucleosides were obtained via microwave promoted aromatic nucleophilic substitution, whereas the S-arylated triazole nucleosides were synthesized via C-S coupling reaction using our newly developed mixed ligand Pd catalyst (Pd2(dba)3/Xantphos/CyPF-tBu). The concept of the mixed ligand catalyst system is extremely advantageous and rewarding, offering a unique opportunity to rationally combine ligands with complementary features in order to promote the reactions with challenging substrates which are otherwise difficult to proceed. Finally, in order to improve bioavailability of the active triazole nucleoside analogues identified in our group, I have attempted to conjugate the triazole nucleoside to an amphiphilic dendrimer in the view to establishing an effective drug delivery system and offering a better bioavailability.

In komplexen Grundwasserleitern lassen sich grundlegende Informationen zur Abgrenzung von Quelleinzugsgebieten, zur Ableitung von Grundwasserfließrichtungen oder zur Bewertung der Vulnerabilität nicht allein über konventionelle hydrogeologische Methoden (beispielsweise Grundwassergleichenpläne, Quellschüttungsmessungen, Pumpversuche) gewinnen, so dass vielfach ergänzend hydrochemische Methoden eingesetzt werden. Zu den gängigen hydrochemischen Methoden gehören Auswertungen der Hauptionenverhältnisse, stabiler und radioaktiver Isotope, von Umwelttracern und Metallen der Seltenen Erden einschließlich des Yttriums sowie der aktive Einsatz künstlicher Markierungsstoffe. Die Anwendung gängiger hydrochemischer Methoden ist durch natürliche oder anthropogene Hintergrundkonzentrationen, die die Ausbildung eines ausreichenden Kontrasts behindern können, limitiert. Da diese Methoden meist nur an der Quelle als integrales Signal des gesamten Einzugsgebiets ansetzen, kann die Abgrenzung des Einzugsgebiets nur indirekt durch die Abschätzung von Volumina und darauf aufbauender Abschätzung der Flächengröße vorgenommen werden. Zur konkreten Lokalisierung der Einzugsgebietsgrenzen und der Ableitung von Grundwasserfließrichtungen sind also zusätzliche Informationen notwendig. Durch die menschliche Produktion organischer Verbindungen steht ein riesiges Spektrum potentieller Indikatoren zur Verfügung, das die Anzahl der bei etablierten Methoden eingesetzten Stoffe um ein Vielfaches übertrifft. Aufgrund ihrer rein anthropogenen Herkunft haben organische Spurenstoffe keine natürlichen Hintergrundkonzentrationen und sind daher bereits auf einem sehr geringen Konzentrationsniveau nutzbar. Im Gebiet der „Waldecker Scholle“ konnten sowohl die räumliche Verteilung organischer Spurenstoffe als auch deren saisonale Konzentrationsschwankungen in einem komplexen Grundwassersystem mit moderat verkarsteten Grundwasserleitern untersucht werden. Die auftretenden Stoffmuster reflektieren die hydrogeologischen Verhältnisse und können zur Lokalisierung von Quelleinzugsgebietsgrenzen genutzt werden. Weitere Hinweise liefern die organischen Spurenstoffe zur Identifikation von punktuellen Eintragsquellen und zur Ausbreitung der aus Punktquellen freigesetzten Stoffe im Grundwasserleiter sowie zum Attenuationspotential dieser Stoffe. Weiterhin kann die hydraulische Wirksamkeit von geringleitenden Zwischenschichten und Störungszonen mittels Identifikation einer Fließkomponente mit einer Verweilzeit von mehr als 20 Jahren abgeschätzt werden. Auch Annahmen hinsichtlich der Vulnerabilität lassen sich validieren. Der Vergleich mit dem hydrogeologisch gut untersuchten Einzugsgebiet der Gallusquelle, zeigt, dass Stoffgruppen wie Triazine und Triazole eine weite Verbreitung haben, andere Stoffe jedoch an bestimmte Gegebenheiten im Gebiet gebunden sind (beispielsweise Altablagerungen, Kanalsystem). Außerdem bestätigt sich in beiden Gebieten, dass das Auftreten von Stoffen sowohl von den Stoffeigenschaften als auch von den hydrogeologischen Eigenschaften abhängig ist. Das bedeutet, dass die Art der in einer Karstquelle auftretenden Stoffe selbst ohne aufwändige zeitlich hochaufgelöste Beprobung bereits Rückschlüsse auf Systemeigenschaften zulässt. Die vorliegende Arbeit zeigt somit, dass organische Spurenstoffe bereits auf der Untersuchungsebene des konzeptionellen Modells wertvolle Indikatoren zur Charakterisierung komplexer Grundwassersysteme sein können. Die große Menge an zur Verfügung stehenden Stoffen bietet die Möglichkeit, bestimmte Stoffe auszuwählen, die die jeweiligen Systemcharakteristika widerspiegeln. Mit organischen Spurenstoffen können sowohl Grundwasserkomponenten unterschiedlicher Verweilzeiten von wenigen Tagen bis zu mehreren Jahrzehnten identifiziert werden als auch räumliche Zusammenhänge von wenigen Metern bis über Einzugsgebietsgrenzen hinaus untersucht werden. Die Einbeziehung organischer Spurenstoffe in die Erkundungsstrategien komplexer Grundwassersysteme hat daher ein vielversprechendes zukunftsweisendes Potential.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Neste trabalho foi realizada a modificação química do poli(cloreto de vinila) (PVC) pela sua reação com azida de sódio, onde alguns dos seus átomos de cloro foram substituídos por azidas. Em seguida o grupo incorporado foi transformado em triazóis por uma reação de cicloadição 1,3 entre o polímero modificado e propiolato de etila, sendo a reação catalisada por iodeto de cobre. Essas reações foram conduzidas sob aquecimento convencional e empregando irradiação de micro-ondas. Inicialmente, a reação incorporou 20% de triazol no PVC, sendo avaliadas as condições reacionais ideais. Essas condições foram usadas para a formação de novos copolímeros com diferentes teores de triazóis incorporados. Os produtos obtidos foram usados para o suporte de paládio que é utilizado como catalisador na reação de Suzuki-Miyaura. Todos os copolímeros foram caracterizados por espectroscopia na região do infravermelho com transformada de Fourier (FTIR) / In this work was performed the chemical modification of poly(vinyl chloride) (PVC) by its reaction with sodium azide, in which some of their chlorine atoms has been replaced with azides. Then the azide group was converted to 1,2,3-triazoles by a 1,3-cycloaddition reaction between the modified polymer and ethyl propiolate, the reaction was catalyzed by copper iodide. These reactions were conducted using conventional heating and microwave irradiation. Initially, the reaction incorporated triazole in 20% of PVC, the optimal reaction conditions was evaluated. These conditions were used for the formation of new copolymers with different amounts of incorporated triazoles. The products obtained were used as a support for palladium, which is used as a catalyst in Suzuki-Miyaura reaction. All copolymers were characterized by infrared spectroscopy, Fourier transform spectroscopy (FTIR)

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Neste trabalho foi realizada a modificação química do poli(cloreto de vinila) (PVC) pela sua reação com azida de sódio, onde alguns dos seus átomos de cloro foram substituídos por azidas. Em seguida o grupo incorporado foi transformado em triazóis por uma reação de cicloadição 1,3 entre o polímero modificado e propiolato de etila, sendo a reação catalisada por iodeto de cobre. Essas reações foram conduzidas sob aquecimento convencional e empregando irradiação de micro-ondas. Inicialmente, a reação incorporou 20% de triazol no PVC, sendo avaliadas as condições reacionais ideais. Essas condições foram usadas para a formação de novos copolímeros com diferentes teores de triazóis incorporados. Os produtos obtidos foram usados para o suporte de paládio que é utilizado como catalisador na reação de Suzuki-Miyaura. Todos os copolímeros foram caracterizados por espectroscopia na região do infravermelho com transformada de Fourier (FTIR) / In this work was performed the chemical modification of poly(vinyl chloride) (PVC) by its reaction with sodium azide, in which some of their chlorine atoms has been replaced with azides. Then the azide group was converted to 1,2,3-triazoles by a 1,3-cycloaddition reaction between the modified polymer and ethyl propiolate, the reaction was catalyzed by copper iodide. These reactions were conducted using conventional heating and microwave irradiation. Initially, the reaction incorporated triazole in 20% of PVC, the optimal reaction conditions was evaluated. These conditions were used for the formation of new copolymers with different amounts of incorporated triazoles. The products obtained were used as a support for palladium, which is used as a catalyst in Suzuki-Miyaura reaction. All copolymers were characterized by infrared spectroscopy, Fourier transform spectroscopy (FTIR)

Indiana University-Purdue University Indianapolis (IUPUI) / Candida albicans and Candida glabrata are opportunistic human pathogens that are the leading cause of fungal infections, which are increasingly becoming the leading cause of sepsis in immunosuppressed individuals. C. glabrata in particular has become a significant concern due to the increase in clinical isolates that demonstrate resistance to triazole antifungal drugs, the most prevalent treatment for such infections. Triazole drugs target the ERG11 gene product and prevent C-14 demethylation of the first sterol intermediate, lanosterol, preventing the production of the pathways end product ergosterol. Ergosterol is required by yeast for cell membrane fluidity and cell signaling. Furthermore, C. glabrata, and not C. albicans, has been reported to utilize cholesterol as a supplement for growth. Although drug resistance is known to be caused by an increase in expression of drug efflux pumps, we hypothesize a second mechanism: that the overuse of triazole drugs has lead to the increase of resistance by C. glabrata through a 2-step process: 1) the accumulation of ergosterol auxotrophic mutations and 2) mutants able to take up exogenous cholesterol anaerobically in the body acquire a second mutation allowing uptake of cholesterol aerobically. Two groups of sterol auxotrophic C. glabrata clinical isolates have been reported to take up sterol aerobically but do not produce a sterol precursor. Sterol auxotrophs have been created in C. glabrata by disrupting different essential genes (ERG1, ERG7, ERG11, ERG25, and ERG27) in the ergosterol pathway to assess which ergosterol mutants will take up sterols aerobically. Random and site-directed mutagenesis was also completed in ERG25 of Saccharmoyces cerevisiae. The ERG25 gene encodes a sterol C-4 methyloxidase essential for sterol biosynthesis in plants, animals, and yeast. This gene functions in turn with ERG26, a sterol C-3 dehydrogenase, and ERG27, a sterol C-3 keto reductase, to remove two methyl groups at the C-4 position on the sterol A ring. In S. cerevisiae, ERG25 has four putative histidine clusters, which bind non-heme iron and a C-terminal KKXX motif, which is a Golgi to ER retrieval motif. We have conducted site-directed and random mutagenesis in the S. cerevisiae wild-type strain SCY876. Site-Directed mutagenesis focused on the four histidine clusters, the KKXX C-terminal motif and other conserved amino acids among various plant, animal, and fungal species. Random mutagenesis was completed with a procedure known as gap repair and was used in an effort to find novel changes in enzyme function outside of the parameters utilized for site-directed mutagenesis. The four putative histidine clusters are expected to be essential for gene function by acting as non-heme iron binding ligands bringing in the oxygen required for the oxidation-reduction in the C-4 demethylation reaction.

[pt] Por ser uma doença genética, resultado de uma mutação em um gene específico, que gera proteínas (CFTR) defeituosas, a Fibrose Cística é uma patologia difícil de ser tratada. Os custos para os tratamentos atualmente disponíveis são altos, sem os quais, porém, a gravidade da doença tende a crescer ainda mais. Por esse motivo, novos tratamentos farmacológicos vêm surgindo, como o Trikafta (marca registrada), uma combinação tripla de fármacos com ação sinérgica (elexacaftor, ivacaftor e tezacaftor). Porém, esse medicamento ainda não é disponível no Brasil e o acesso aos tratamentos, em geral, são onerosos. Sendo assim, este trabalho visa a síntese de compostos 1,2,3-triazóis, com possível atividade biológica frente a proteína CFTR, sugerida por ancoragem molecular. Este trabalho também visa selecionar as melhores moléculas quanto aos perfis farmacocinéticos e toxicológicos, avaliados por ferramentas computacionais como swissADME e VirtualToxLab, respectivamente. Dessa forma, a estratégia sintética para a obtenção dos compostos consiste em duas etapas sintéticas. A primeira, envolve a síntese da enaminona – (E)-3-(dimetilamino)acrilaldeido (3a-d) – por organocatálise, a partir de L-prolina e DMA-DMF (1,1-dimetoxi-N,N-dimetillmetanamina) (1). A segunda etapa inclui a reação de cicloadição 1,3-dipolar onpot entre as azidas (5a-h) e as enaminonas previamente obtidas. Assim, foi possível obter 1,2,3-triazóis 1,4-substituídos (6a-k), com rendimentos de 5 a 96 por cento. Dentre eles, a molécula 6k, N-(2-(1-(4-metoxifenil)-1H-1,2,3-triazol-4-carbonil)fenil)acetamida), destacou-se quanto aos perfis toxicológicos e também pelos resultados observados nos estudos de ancoragem molecular. Os espectros de RMN de 1H e 13C RMN confirmaram a obtenção das estruturas. / [en] Because it is a genetic disease, the result of a mutation in a specific gene, which generates defective proteins (CFTR), Cystic Fibrosis is a pathology that is difficult to be treated. The costs for currently available treatments are high, without which, however, the severity of the disease tends to increase even more. For this reason, new pharmacological treatments are emerging, such as Trikafta (trademark), a triple combination of drugs with synergistic action (elexacaftor, ivacaftor and tezacaftor). However, this drug is not yet available in Brazil and access to treatments, in general, is expensive. Therefore, this work aims at the synthesis of 1,2,3-triazole compounds, with possible biological activity against the CFTR protein, proposed by molecular anchoring. This work also aims to select the best molecules in terms of pharmacokinetic and toxicological profiles, evaluated by computational tools such as swissADME and VirtualToxpot, respectively. Thus, the synthetic strategy for obtaining the compounds consists of two synthetic steps. The first involves the synthesis of enaminone - (E)-3-(dimethylamino) acrylaldehyde (3a-d) - by organocatalysis, starting from L- proline and DMA-DMF (1,1-dimethoxy-N, N-dimethylmethanamine) (1). The second stage includes the 1,3-dipolar onpot cycloaddition reaction between the azides (5a-h) and the previously obtained enaminones. Thus, it was possible to obtain 1,4-substituted 1,2,3-triazoles (6a-k), with yields of 5 to 96 percent. Among them, the molecule 6k, N- (2- (1- (4-methoxyphenyl) -1H-1,2,3-triazol-4-carbonyl) phenyl) acetamide), stood out in terms of toxicological profiles and also by results observed in molecular anchorage studies. The 1H and 13C NMR NMR spectra confirmed the structures obtained.

Целью выпускной квалификационной работы является комплексное исследование интегральных антиоксидантных параметров препаратов комбинированного действия для терапии вирусных и нейродегенеративных заболеваний. Были изучены пути образования свободных радикалов, рассмотрены антиоксидантные подходы в терапии различных заболеваний. С использованием предложенных потенциометрических методов была исследована антиоксидантная (АОЕ) и антирадикальная (АРЕ) емкость синтезированных триазолов и имидазолов, модифицированных полифенолами. АОЕ определяли потенциометрическим методом с использованием окислителя нерадикальной природы – K3[Fe(CN)6]/K4[Fe(CN)6], АРЕ оценивали потенциометрическим методом с использованием радикал-генерирующей системы 2,2´-азобис(2-метилпропионамидин) дигидрохлорида (ААРН). Стехиометрические коэффициенты ингибирования изученных триазолов принимают значения от 0 до 15, имидазолов от 0 до 5 в зависимости от количества активных групп в молекуле антиоксиданта, их расположением и с механизмом обрыва цепей на антиоксиданте. Были проведены корреляционные исследования с применением независимых спектрофотометрических методов. / Objective of the work: comprehensive study of integral antioxidant parameters of combined action drugs for the treatment of viral and neurodegenerative diseases. We have considered ways to form free radicals and antioxidant approaches in therapy of various diseases. In the process of work we investigated the antioxidant parameters adducts of triazole and imidazoles modified with polyphenols. Particularly, the determination of antioxidant capacity with oxidizing agents of a radical (2,2'-azobis (2-methylpropionamidine) dihydrochloride (AAPH)) and non-radical nature (K3[Fe(CN)6]/K4[Fe(CN)6) was performed by using the potentiometric method. Stoichiometric inhibition coefficients of the studied triazoles take values from 0 to 15, imidazoles – from 0 to 5, depending on the number of active groups in the antioxidant molecule, their location and the mechanism of chain termination on the antioxidant. Spectrophotometric studies were carried out using the reactions of the interaction of antioxidants with a stable radical 2,2-diphenyl-1-picrylhydrazyl (DPPH•) and reagent Folin-Ciocalteu to confirm the correctness of the results.

Cyanoform (tricyanomethane) is one of the strongest carbon-based organic acids reported in text books of organic chemistry, which has evaded synthesis and isolation in its free state, since 120 years. In this dissertation, the acid-free synthesis of cyanoform by an absolutely new approach has been discussed. Generation of the elusive molecule, cyanoform from the photolysis and thermolysis of 2-(azidomethylidene)malononitrile, has been confirmed at very low temperatures by 1H NMR, 13C NMR, 15N NMR, and the relevant 2D NMR spectroscopic techniques. Moreover, it has been proved that cyanoform is relatively stable, but can be detected only below –85 oC, and not at high temperatures (at –45 oC, as has been reported in literature), because of a rapid equilibration with an another species. Furthermore, the chemistry of cyanoform in the ring enlargement reactions with various highly strained epoxides, azirines, and aziridines, via the highly reactive dicyanoketenimine intermediate, as well as its Michael addition reactions with different α,β-unsaturated carbonyl compounds has been well explored. In addition, the synthesis of N1-substituted 1,2,3-triazoles and study of their rearrangement to the corresponding N2-substituted 1,2,3-triazoles, under thermal and nucleophile-catalyzed reaction conditions, has been well investigated. / Cyanoform (Tricyanomethan) ist eine der stärksten in der Literatur beschriebenen organischen Kohlenstoffsäuren, welche sich seit 120 Jahren einer erfolgreichen Synthese und Isolierung entzogen hat. In dieser Arbeit wird die säurefreie Synthese des Cyanoforms mittels eines neuartigen Ansatzes diskutiert. Die Bildung des schwer fassbaren Moleküls durch Photolyse und Thermolyse von 2 (Azidomethyliden)malonitril ist bei tiefen Temperaturen durch 1H-NMR, 13C-NMR, 15N-NMR und relevante 2D-NMR-Methoden bestätigt worden. Es konnte bewiesen werden, dass Cyanoform relative stabil ist, aber erst unterhalb von –85 °C detektierbar ist und nicht bereits bei hӧherer Temperature (bei –45 °C, wie es in der Literatur beschrieben wurde) bedingt durch die rasche Äquilibrierung mit einer weiteren Species. Des Weiteren wurde die Reaktivität von Cyanoform in Ringerweiterungsreaktionen mit verschiedenen, stark gespannten Epoxiden, Azirinen und Aziridinen untersucht, wobei das hoch reaktive Dicyanoketenimin-Intermediat durchlaufen wird. Auch die Michael-Addition an α,β ungesättigte Carbonylverbindungen wurde ausführlich untersucht. Zusätzlich wurde die Synthese N1 substituierter 1,2,3-Triazole und deren Umlagerung in N2 substituierte 1,2,3-Triazole unter thermischen und nucleophil-katalysierten Bedingungen erforscht.