Les travaux réalisés pendant cette thèse ont porté sur deux thématiques indépendantes.Les deux premières parties concernent la thématique « alcaloïdes de Vinca », molécules d’origine naturelle aux propriétés anticancéreuses. Les travaux ont tout d’abord porté sur la synthèse d’analogues oxygénés de la 20,20-difluorocatharanthine, comme précurseurs d’alcaloïdes dimères originaux de Vinca. Bien que les voies de synthèses explorées n’aient pas conduit aux dérivés oxygénés souhaités, les différents résultats obtenus ont cependant permis de montrer que la présence du groupement gem-difluoré sur le squelette de la catharanthine changeait dramatiquement la réactivité du substrat de manière imprévisible. La deuxième partie de ce travail a été dédiée à l’élucidation du mécanisme de fluoration d’alcaloïdes dimères de Vinca en milieu superacide. Le marquage isotopique au deutérium a permis de discriminer deux hypothèses mécanistiques et de valider le mécanisme de fluoration passant par une migration 1,2 d’hydrure dont la contribution minimale est de 20 %. Enfin, la troisième partie de ce travail a été consacrée à la synthèse asymétrique de la (R)-méquitazine. La synthèse de cette dernière s’est basée sur la chiralité déjà « imprimée » dans le squelette d’alcaloïdes de cinchona. La synthèse de la (R)-méquitazine dont les excès énantiomériques finaux sont supérieurs à 99% a été conclue en 8 étapes à partir de la quinine, confirmant le contrôle total du centre asymétrique tout au long de la synthèse. / The work carried out during this thesis has focused on two independent parts.The first two sections have dealt with the “Vinca alkaloids” part, natural products with anticancer properties. Firstly, the work has focused on the synthesis of oxygenated analogs of the 20,20-difluorocatharanthine as precursors of original dimeric Vinca alkaloid. Although explored synthesis pathways have not led to the desired oxygenated derivatives, different results has enabled to show that the presence of the gem-difluoro groupment on catharanthine skeleton dramatically changed the reactivity of the substrate in an unpredictable manner. The second part of this work was dedicated to the elucidation of the mechanism of fluorination of alkaloids dimers of Vinca in superacid medium. Isotopic labelling with deuterium has allowed to discriminate two mechanistic hypotheses and to validate the mechanism of fluoridation via a 1,2-hydride migration whose minimum contribution is 20 %.Finally, the third part of this work has been devoted to the asymmetric synthesis of (R)- mequitazine. The synthesis is based on the chirality already "printed" into the skeleton of cinchona alkaloids. Synthesis of (R)-mequitazine with greater than 99% final enantiomeric excess was reached in 8 steps from quinine, confirming full control of the asymmetrical centre during the synthesis.

Thesis submitted in fulfilment of the requirements for the Degree of Master of Technology: Organic Chemistry, Durban University of Technology, 2011. / Malaria, the most prevalent parasitic disease, is considered a neglected disease owing to insufficient research and development in synthesis and therapy worldwide. Therapy failures are frequent and are due to a variety of factors such as the intrinsic characteristics of the disease, conditions of transmission, and the difficult control of spreading through tropical areas. Primary factors are the complexity of the parasite life cycle and the development of drug resistance. Another critical factor is the increasing number of immune-compromised patients that suffer from malaria and human immunodeficiency virus (HIV) co-infections. Most of the drugs currently available to treat malaria are quinoline derivatives modelled on the quinine molecule, found in the bark of Cinchona trees. Over the last 50 years the use of quinine has declined owing to the development of synthetic 4-aminoquinolines such as chloroquine. However, the malaria parasite is rapidly becoming resistant to the drugs currently available. Recently bisquinoline compounds were found more potent than chloroquine against both chloroquine-sensitive and resistant strains of malaria; this improved efficacy and prompted an increased interest in the design of these anti-malarial drugs. Although several synthetic methods are available to synthesise bisquinolines, we report the synthesis of bisquinolines from simple, readily available and cost- effective starting compounds. The synthesis was accomplished in four reaction steps using the Claisen condensation, Vilsmeir-Haack reaction, formation of a Schiff base and thermal cyclization, sequentially. We used a conventional energy source and microwave irradiation for the synthesis, wherever possible, of 2, 4-dichloro-3, 4'-biquinoline and 2, 4-dichloro-7'-methoxy-3, 4'-biquinoline. In the first step, 3-acyl-2, 4-dihydroxyquinoline is synthesised from an equimolar mixture of methyl-2-aminobenzoate and ethyl acetoacetate by microwave irradiation for 3 minutes; the yield is 90 % whereas by 6 hours refluxing the yield is 75 %. This is followed by the synthesis of 3-chloro-3-(2,4-dichloroquinolin-3yl) acrylaldehyde, by combining DMF and POCl3 at 00C to form the electrophile which reacts with 3-acyl-2,4-dihydroxyquinoline under microwave irradiation for 5 minutes; the yield is 65 % whereas by 6 hours refluxing the yield is 50 %. In the next step, several protocols to prepare a Schiff base 3-chloro-3-(2, 4-dichloroquinolin-3-yl) allylidene aniline are investigated with the best yield of 75% obtained by microwave irradiation for 5 minutes. Subsequently three aniline derivatives viz, 4-methoxyaniline, 4-chloroaniline and 4-methylaniline, are used as substrate to prepare 3-chloro-3-(2,4-dichloroquinolin-3-yl) allylidene-4-methoxyaniline, 3-chloro-3-(2 ,4-dichloroquinolin-3-yl) allylidene-4-methylaniline and 3-chloro-3-(2, 4-dichloroquinolin-3-yl) allylidene-4-chloro aniline at 68, 78 and 64 % yield, respectively. In the final step, 2, 4-dichloro-3, 4'-biquinoline is prepared; several methods were investigated, however, the best yield is 24 % which is obtained under alkaline conditions in the presence of K2CO3 and DMF by microwave irradiation for 10 minutes. The 2, 4-dichloro-7'-methoxy-3, 4'-biquinoline derivative is also prepared in 18 % yield under the same alkaline conditions. The outline of the total synthesis of bisquinoline is presented graphically below. / National Research Fund.

Submitted by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2016-09-22T14:44:04Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Luana Michels.pdf: 1171595 bytes, checksum: b9997bd5e324e4be251a83985c506a7c (MD5) / Approved for entry into archive by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2016-09-22T14:44:18Z (GMT) No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Luana Michels.pdf: 1171595 bytes, checksum: b9997bd5e324e4be251a83985c506a7c (MD5) / Made available in DSpace on 2016-09-22T14:44:18Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Luana Michels.pdf: 1171595 bytes, checksum: b9997bd5e324e4be251a83985c506a7c (MD5) Previous issue date: 2016-03-11 / O aumento da resistência do Plasmodium falciparum dificulta o tratamento da malária, o que leva a utilização de doses mais elevadas dos fármacos e subsequente toxicidade. As nanopartículas com superfície modificada têm sido estudadas com a finalidade de alterar a performance in vivo dos fármacos. O objetivo do presente trabalho foi desenvolver, caracterizar e avaliar a eficácia in vitro, in vivo e a farmacocinética das nanopartículas contendo quinina (QN) com diferentes características de superfície: nanocápsulas revestidas com polissorbato 80; nanocapsulas revestidas com PEG e nanocapsulas preparadas com Eudragit®. As suspensões foram preparados pelo método de nanoprecipitação e caracterizados de acordo com o diâmetro, índice de polidispersão, pH, potencial zeta, teor, taxa de encapsulação e microscopia de força atômica. As nanopartículas que apresentaram os melhores resultados na caracterização e eficácia in vitro, foram escolhidas para a avaliação da farmacocinética e eficácia in vivo, utilizando ratos Wistar e camundongos infectados com o P. berghei. As nanocápsulas apresentaram os melhores resultados na caracterização físico-química, com diâmetro adequado, população monodispersa, potencial zeta mais distante de zero, maior taxa de encapsulação e penetração intra-eritrocitária. Houve um aumento significativo no t1/2 de eliminação de todas as nanocápsulas avaliadas em relação à QN livre. Na eficácia in vivo, as nanocápsulas catiônicas aumentaram a sobrevida em relação à salina e à QN livre, demonstrando que o fármaco incorporado na suspensão com características catiônicas pode alterar a eficácia da QN apresentando-se como uma alternativa potencial para o tratamento da malária. / The increase of Plasmodium falciparum resistance difficult the treatment of malaria, and the use of higher doses of the drug induce toxicity. The coating of nanoparticles have been studied with the purpose of improve the in vivo performance of drugs. The aim of this study was to develop, characterize and evaluate the efficacy in vitro, in vivo and pharmacokinetics of quinine (QN) loaded-nanoparticles with different surface characteristics: polysorbate 80 coated-nanocapsules; PEG coated-nanocapsules and nanocapsules prepared with Eudragit® RS 100. The suspensions were prepared by nanoprecipitation method and characterized according to the diameter, polydispersity, pH, zeta potential, content encapsulation rate and atomic force microscopy. The nanoparticles showed the best results on the characterization and in vitro efficacy were chosen for evaluating the in vivo efficacy and pharmacokinetics, using Wistar rats and mice infected with P. berghei. The nanocapsules showed the best results in the physical-chemical characterization, with appropriate diameter, monodisperse population, zeta potential distant from zero, the higher rate of encapsulation and intra-erythrocyte penetration. There was a significant increase in t1/2 of all nanocapsules evaluated in comparison to free QN. On the efficacy in vivo, cationic nanocapsules increased the survival rate compared to saline and to the free QN, demonstrating that the drug incorporated in the suspension with cationic characteristics can alter the efficacy of QN presenting as a potential alternative for the treatment of malaria.

Les travaux réalisés pendant cette thèse ont porté sur deux thématiques indépendantes.Les deux premières parties concernent la thématique " alcaloïdes de Vinca ", molécules d'origine naturelle aux propriétés anticancéreuses. Les travaux ont tout d'abord porté sur la synthèse d'analogues oxygénés de la 20,20-difluorocatharanthine, comme précurseurs d'alcaloïdes dimères originaux de Vinca. Bien que les voies de synthèses explorées n'aient pas conduit aux dérivés oxygénés souhaités, les différents résultats obtenus ont cependant permis de montrer que la présence du groupement gem-difluoré sur le squelette de la catharanthine changeait dramatiquement la réactivité du substrat de manière imprévisible. La deuxième partie de ce travail a été dédiée à l'élucidation du mécanisme de fluoration d'alcaloïdes dimères de Vinca en milieu superacide. Le marquage isotopique au deutérium a permis de discriminer deux hypothèses mécanistiques et de valider le mécanisme de fluoration passant par une migration 1,2 d'hydrure dont la contribution minimale est de 20 %. Enfin, la troisième partie de ce travail a été consacrée à la synthèse asymétrique de la (R)-méquitazine. La synthèse de cette dernière s'est basée sur la chiralité déjà " imprimée " dans le squelette d'alcaloïdes de cinchona. La synthèse de la (R)-méquitazine dont les excès énantiomériques finaux sont supérieurs à 99% a été conclue en 8 étapes à partir de la quinine, confirmant le contrôle total du centre asymétrique tout au long de la synthèse.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 6 uppsatser.

Objetivos: Desenvolver, caracterizar e avaliar a eficácia in vivo e o perfil farmacocinético de suspensões de nanocápsulas (NC) poliméricas contendo quinina (QN). Metodologia: As NC-QN foram preparadas através de nanoprecipitação com diferentes concentrações de QN: 2 (NC2-QN), 3 (NC3-QN) e 4 mg/mL (NC4-QN). A NC4-QN também foi revestida com quitosana. Todas as formulações foram caracterizadas através de taxa de encapsulação, teor, diâmetro, índice de polidispersão, potencial zeta e pH, sendo a estabilidade avaliada por 30 dias. A avaliação da eficácia foi realizada com diferentes doses de cada formulação, em modelo de malária experimental em ratos Wistar infectados com Plasmodium berguei. A dose de NC-QN com a qual se obteve 100 % de cura dos animais foi selecionada para a avaliação farmacocinética. Nesses experimentos, os animais sadios ou infectados receberam a QN livre ou a NC2-QN, 25 mg/kg, iv bolus. As amostras de plasma coletadas em tempos pré-determinados foram quantificadas por CLAE com método validado para a determinação da QN. Os protocolos com animais foram aprovados pelo Comitê de Ética em Pesquisa da UFRGS (#2005477). Resultados e discussão: As suspensões coloidais preparadas com diferentes concentrações de QN apresentaram diâmetro adequado, população modispersa, potencial zeta diferente de zero, doseamento e taxa de encapsulação superior a 90 %. Somente a NC2-QN, na dose de 75 mg/kg/dia, q8h, curou todos os animais. Nas doses de 30 e 60 mg/kg/dia, q8h, 28,6 e 85,7% dos animais sobreviveram, respectivamente, com a NC2-QN. Houve uma diminuição significativa no t½ das NC2-QN (32,9 ± 8,9 min) em relação ao fármaco livre (69,8 ± 44,6 min), no grupo de animais infectados (α = 0,05) em função de uma tendência de aumento do CLtotal (7,1 ± 3,3 versus 9,9 ± 2,1 L/h/kg) do fármaco nanoencapsulado. Conclusões: A nanoencapsulação da QN reduziu a dose efetiva do fármaco no modelo animal avaliado em 30 % e aumentou a sobrevivência dos animais infectados em cerca de 60 %, apresentando-se como uma alternativa potencial para o tratamento da malária. / Objectives: The aims of this study were to develop and characterize polymeric nanocapsules (NC) containing quinine (QN) and to evaluate their efficacy in vivo as well as the pharmacokinetic profile of the nanoencapsulated drug. Methodology: NC-QN were prepared by nanoprecipitation with different drug concentration 2 (NC2- QN), 3 (NC3-QN) and 4 mg/mL (NC4-QN). All formulations were characterized in terms of encapsulation efficacy, drug loading, zeta potential, particle size, polydispersion index, and pH. The stability nanocapsules suspensions were evaluated during 30 days. An experimental malaria model with Plasmodium berghei was used to evaluate NC-QN efficacy in Wistar rats. Different doses were tested for each formulation. The pharmacokinetic evaluation was performed with the dose of NC–QN which presented 100 % efficacy in malaria model. The NC2-QN or QN free were administrated by i.v. route (25 mg/kg) to health and infected rats. Blood samples were collected at pre-determinated time points and quantified by an HPLC validated method. Animal protocols were approved by UFRGS Ethics in Research Committee (# 2005477). Results and discussion: All suspensions presented adequate particle size, monodisperse population, negative zeta potential, drug content and encapsulation efficiency higher than 90 %. The formulation NC2-QN (75 mg/kg/day) administrated q8h daily during 7-9 days post-infection cured all infected rats. For NC2-QN, 30 and 60 mg/kg/day, q8h, 28.6 and 85.7 % of survival were observed, respectively. NC2-QN presented significant decrease in QN t½ compared to the free drug (32.9 ± 8.9 min and 69.8 ± 44.6 min, respectively), in infected rats (α = 0,05). This occurs due to the tendency of increase in CLtotal (7.1 ± 3.3 to 9.9 ± 2.1 L/h/kg, for free QN and NC2-QN, respectively). CLtotal increased in the encapsulated group. Conclusion: Nanoencapsulation reduced QN effective dose in 30 % and increased in 60 % the survival of the infected animals. Theses results indicate that NC-QN is a potential strategy to be investigated for malaria treatment.

Objetivos: Desenvolver, caracterizar e avaliar a eficácia in vivo e o perfil farmacocinético de suspensões de nanocápsulas (NC) poliméricas contendo quinina (QN). Metodologia: As NC-QN foram preparadas através de nanoprecipitação com diferentes concentrações de QN: 2 (NC2-QN), 3 (NC3-QN) e 4 mg/mL (NC4-QN). A NC4-QN também foi revestida com quitosana. Todas as formulações foram caracterizadas através de taxa de encapsulação, teor, diâmetro, índice de polidispersão, potencial zeta e pH, sendo a estabilidade avaliada por 30 dias. A avaliação da eficácia foi realizada com diferentes doses de cada formulação, em modelo de malária experimental em ratos Wistar infectados com Plasmodium berguei. A dose de NC-QN com a qual se obteve 100 % de cura dos animais foi selecionada para a avaliação farmacocinética. Nesses experimentos, os animais sadios ou infectados receberam a QN livre ou a NC2-QN, 25 mg/kg, iv bolus. As amostras de plasma coletadas em tempos pré-determinados foram quantificadas por CLAE com método validado para a determinação da QN. Os protocolos com animais foram aprovados pelo Comitê de Ética em Pesquisa da UFRGS (#2005477). Resultados e discussão: As suspensões coloidais preparadas com diferentes concentrações de QN apresentaram diâmetro adequado, população modispersa, potencial zeta diferente de zero, doseamento e taxa de encapsulação superior a 90 %. Somente a NC2-QN, na dose de 75 mg/kg/dia, q8h, curou todos os animais. Nas doses de 30 e 60 mg/kg/dia, q8h, 28,6 e 85,7% dos animais sobreviveram, respectivamente, com a NC2-QN. Houve uma diminuição significativa no t½ das NC2-QN (32,9 ± 8,9 min) em relação ao fármaco livre (69,8 ± 44,6 min), no grupo de animais infectados (α = 0,05) em função de uma tendência de aumento do CLtotal (7,1 ± 3,3 versus 9,9 ± 2,1 L/h/kg) do fármaco nanoencapsulado. Conclusões: A nanoencapsulação da QN reduziu a dose efetiva do fármaco no modelo animal avaliado em 30 % e aumentou a sobrevivência dos animais infectados em cerca de 60 %, apresentando-se como uma alternativa potencial para o tratamento da malária. / Objectives: The aims of this study were to develop and characterize polymeric nanocapsules (NC) containing quinine (QN) and to evaluate their efficacy in vivo as well as the pharmacokinetic profile of the nanoencapsulated drug. Methodology: NC-QN were prepared by nanoprecipitation with different drug concentration 2 (NC2- QN), 3 (NC3-QN) and 4 mg/mL (NC4-QN). All formulations were characterized in terms of encapsulation efficacy, drug loading, zeta potential, particle size, polydispersion index, and pH. The stability nanocapsules suspensions were evaluated during 30 days. An experimental malaria model with Plasmodium berghei was used to evaluate NC-QN efficacy in Wistar rats. Different doses were tested for each formulation. The pharmacokinetic evaluation was performed with the dose of NC–QN which presented 100 % efficacy in malaria model. The NC2-QN or QN free were administrated by i.v. route (25 mg/kg) to health and infected rats. Blood samples were collected at pre-determinated time points and quantified by an HPLC validated method. Animal protocols were approved by UFRGS Ethics in Research Committee (# 2005477). Results and discussion: All suspensions presented adequate particle size, monodisperse population, negative zeta potential, drug content and encapsulation efficiency higher than 90 %. The formulation NC2-QN (75 mg/kg/day) administrated q8h daily during 7-9 days post-infection cured all infected rats. For NC2-QN, 30 and 60 mg/kg/day, q8h, 28.6 and 85.7 % of survival were observed, respectively. NC2-QN presented significant decrease in QN t½ compared to the free drug (32.9 ± 8.9 min and 69.8 ± 44.6 min, respectively), in infected rats (α = 0,05). This occurs due to the tendency of increase in CLtotal (7.1 ± 3.3 to 9.9 ± 2.1 L/h/kg, for free QN and NC2-QN, respectively). CLtotal increased in the encapsulated group. Conclusion: Nanoencapsulation reduced QN effective dose in 30 % and increased in 60 % the survival of the infected animals. Theses results indicate that NC-QN is a potential strategy to be investigated for malaria treatment.

Objetivos: Desenvolver, caracterizar e avaliar a eficácia in vivo e o perfil farmacocinético de suspensões de nanocápsulas (NC) poliméricas contendo quinina (QN). Metodologia: As NC-QN foram preparadas através de nanoprecipitação com diferentes concentrações de QN: 2 (NC2-QN), 3 (NC3-QN) e 4 mg/mL (NC4-QN). A NC4-QN também foi revestida com quitosana. Todas as formulações foram caracterizadas através de taxa de encapsulação, teor, diâmetro, índice de polidispersão, potencial zeta e pH, sendo a estabilidade avaliada por 30 dias. A avaliação da eficácia foi realizada com diferentes doses de cada formulação, em modelo de malária experimental em ratos Wistar infectados com Plasmodium berguei. A dose de NC-QN com a qual se obteve 100 % de cura dos animais foi selecionada para a avaliação farmacocinética. Nesses experimentos, os animais sadios ou infectados receberam a QN livre ou a NC2-QN, 25 mg/kg, iv bolus. As amostras de plasma coletadas em tempos pré-determinados foram quantificadas por CLAE com método validado para a determinação da QN. Os protocolos com animais foram aprovados pelo Comitê de Ética em Pesquisa da UFRGS (#2005477). Resultados e discussão: As suspensões coloidais preparadas com diferentes concentrações de QN apresentaram diâmetro adequado, população modispersa, potencial zeta diferente de zero, doseamento e taxa de encapsulação superior a 90 %. Somente a NC2-QN, na dose de 75 mg/kg/dia, q8h, curou todos os animais. Nas doses de 30 e 60 mg/kg/dia, q8h, 28,6 e 85,7% dos animais sobreviveram, respectivamente, com a NC2-QN. Houve uma diminuição significativa no t½ das NC2-QN (32,9 ± 8,9 min) em relação ao fármaco livre (69,8 ± 44,6 min), no grupo de animais infectados (α = 0,05) em função de uma tendência de aumento do CLtotal (7,1 ± 3,3 versus 9,9 ± 2,1 L/h/kg) do fármaco nanoencapsulado. Conclusões: A nanoencapsulação da QN reduziu a dose efetiva do fármaco no modelo animal avaliado em 30 % e aumentou a sobrevivência dos animais infectados em cerca de 60 %, apresentando-se como uma alternativa potencial para o tratamento da malária. / Objectives: The aims of this study were to develop and characterize polymeric nanocapsules (NC) containing quinine (QN) and to evaluate their efficacy in vivo as well as the pharmacokinetic profile of the nanoencapsulated drug. Methodology: NC-QN were prepared by nanoprecipitation with different drug concentration 2 (NC2- QN), 3 (NC3-QN) and 4 mg/mL (NC4-QN). All formulations were characterized in terms of encapsulation efficacy, drug loading, zeta potential, particle size, polydispersion index, and pH. The stability nanocapsules suspensions were evaluated during 30 days. An experimental malaria model with Plasmodium berghei was used to evaluate NC-QN efficacy in Wistar rats. Different doses were tested for each formulation. The pharmacokinetic evaluation was performed with the dose of NC–QN which presented 100 % efficacy in malaria model. The NC2-QN or QN free were administrated by i.v. route (25 mg/kg) to health and infected rats. Blood samples were collected at pre-determinated time points and quantified by an HPLC validated method. Animal protocols were approved by UFRGS Ethics in Research Committee (# 2005477). Results and discussion: All suspensions presented adequate particle size, monodisperse population, negative zeta potential, drug content and encapsulation efficiency higher than 90 %. The formulation NC2-QN (75 mg/kg/day) administrated q8h daily during 7-9 days post-infection cured all infected rats. For NC2-QN, 30 and 60 mg/kg/day, q8h, 28.6 and 85.7 % of survival were observed, respectively. NC2-QN presented significant decrease in QN t½ compared to the free drug (32.9 ± 8.9 min and 69.8 ± 44.6 min, respectively), in infected rats (α = 0,05). This occurs due to the tendency of increase in CLtotal (7.1 ± 3.3 to 9.9 ± 2.1 L/h/kg, for free QN and NC2-QN, respectively). CLtotal increased in the encapsulated group. Conclusion: Nanoencapsulation reduced QN effective dose in 30 % and increased in 60 % the survival of the infected animals. Theses results indicate that NC-QN is a potential strategy to be investigated for malaria treatment.

Plasmachemical processes are one of the methods used for wastewater treatment. Sewage and household wastewaters include a variety of organic substances that must be removed to reuse water in industry or households. The aim of this diploma thesisisthe observation of alkaloids decomposition by plasma chemical process. The theoretical part is focused on plasma generation in liquids and characterization of selected alkaloids. The decomposition of caffeine and quinine in direct current electrical discharge in liquid with diaphragm configuration is investigated in this work. The experiments were carried out in a batch reactor divided into two parts by a diaphragm made from ceramic material ShapalTM-M (thickness 3.0 mm, pin-hole diameter 1.0 mm). The stainless steel electrodes of 5×12 cm size were used. The mean electric power was set to 135 W for an operation time of 60 minutes in each experiment. Caffeine solutions (total volume of 4 L) were prepared in concentrations of 10, 25 and 50 ppm, quinine solutions in concentrations of 5, 10 and 15 ppm. The initial conductivity was adjusted by sodium chloride at three different values – 400, 750 or 1000 µS•cm-1. The experimental part consisted also of using analytical methods necessary for compound quantification. Hydrogen peroxide formation during the electrical discharge was determined by colorimetric method based on generation of yellow complex with titanium(IV) sulfate reagent. The caffeine concentration was measured by UV spectrometric method at wavelength 273 nmand thenHPLC/MS analysis was performed. Quinine degradation was monitored by UV-VIS spectrometry and fluorescent measurements. The plasma generation in water solutions induces formation of hydroxyl radical, hydrogen peroxide, oxygen, hydrogen and other reactive species. Hydrogen peroxide is produced and then utilized in degradation of organic compounds and thus lower concentration of H2O2was measured in solution with caffeine and quinine than in solution without alkaloids. However, the situation is different between cathode chamber and anode chamber. There is only negligible amount of H2O2used on degradation in cathode chamber. In contrary, the considerable degradation of caffeine and quinine and diminished concentration of H2O2 was observed in anode chamber.

Cyclodextrins are well known for their ability to encapsulate molecules and have captured the attention of scientists for many years. This ability alone makes cyclodextrins attractive for study, research, and applications in many fields including food, cosmetics, textiles, and the pharmaceutical industry. In this thesis, we specifically look at the ability of the three native cyclodextrins, alpha, beta, and gamma cyclodextrin (α-CD, β-CD, and γ-CD, respectively), to encapsulate the drug molecule, quinine, a small hydrophobic, lipophilic molecule used to treat malaria, leg cramps, and other similar conditions. This encapsulation process is driven by the molecular interactions, which have been studied by NMR techniques at different temperatures (288 K, 293 K, 298 K, 303 K, 308 K) and pH values (7.4, 11.5). These factors (temperature and pH) influence these molecular interactions, which in turn significantly affects the entire encapsulation process. Detailed studies of the influences of temperature and pH on the interactions that drive the encapsulation may suggest some new directions into designing controlled drug release processes. Results obtained throughout the course of this work indicate that β-CD is the best native cyclodextrin to bind quinine, and that binding is best at pH = 11.5. It was found that temperature does not significantly affect the binding affinity of quinine to either α-CD, β-CD, or γ-CD.