Introduction - Malaria is a major global health problem, with more than 500 million reported cases and at least 1 million deaths each year. The main problem with malaria control is the emerging drug resistance. Plasmodium falciparum (P. falciparum) developed widespread resistance to antimalarial drugs such as chloroquine (CQ) and mefloquine, but not to the artemisinins. The World Health Organization (WHO) recommended artemisinin combination therapy (ACT) for the treatment of uncomplicated malaria in all chloroquine resistance areas. However, P. falciparum has recently started to display resistance to these ACTs, highlighting the need for new chemotherapeutic approaches for the treatment of P. falciparum infections. Aims - The aims of this study were: (i) to design and synthesise a new series of antimalarial hybrid drugs, consisting of dihydroartemisinin (DHA) and aminoquinoline moieties bound covalently through different, very distinctive linkers; (ii) to determine the in vitro antiplasmodial activity and cytotoxicity of the synthesised series; (iii) to ascertain whether the in vitro antiplasmodial activity of the promising compounds would be carried over in vivo against Plasmodium vinckei (P. vinckei); and, (iv) to obtain an indication of the pharmacokinetic properties of this class of antimalarial drugs by performing snapshot pharmacokinetic analysis. Methods - DHA was coupled via an aminoethylether bond to various aminoquinolines to give hybrids and hybrid-dimers. CQ-susceptible (D10 and 3D7) and CQ-resistant (Dd2) strains of P. falciparum were used to determine the in vitro antiplasmodial activity. In vitro cytotoxicity was assessed using a mammalian cell-line (Chinese Hamster Ovarian, CHO). The antiproliferative activity of the hybrid-dimers was tested against three cell lines; renal adenocarcinoma (TK-10), breast adenocarcinoma (MCF-7) and melanoma (UACC-62). P. vinckei-infected mice were treated with the hybrid drugs for four days at a dosage of 0.8 mg/kg, 2.5 mg/kg, 7.5 mg/kg or 15 mg/kg intraperitoneally (ip) or orally (po), with 2.7 mg/kg, 8.3 mg/kg, 25 mg/kg or 50 mg/kg, in order to determine their antimalarial activity. A snapshot oral and intravenous (IV) pharmacokinetic study was performed. Results - All compounds were obtained as the 10-β-isomers and were isolated as the oxalate salts. Low nanomolar in vitro antiplasmodial activities were displayed by several compounds in this series, with IC50 values ranging from 5.15 to 29.5 nM, in comparison with the values of 2.09–5.11 nM and 21.54–157.90 nM for each of DHA and CQ respectively. All compounds displayed good selectivity towards P. falciparum in vitro (selectivity index (SI) ≥ 20). Two of the hybrids, featuring non-methylated and methylated two-carbon diaminoalkyl linkers, exerted potent in vivo antimalarial activities, with ED50 values of 1.1 and 1.4 mg/kg by ip route and 12 and 16 mg/kg po, respectively. Long-term monitoring of parasitaemia showed a complete cure of mice (without recrudescence) at 15 mg/kg ip and at 50 mg/kg po for these two hybrids, whereas artesunate was able to provide a complete cure only at 30 mg/kg ip and 80 mg/kg po. Conclusions - These compounds may provide a lead into a new class of antimalarial drugs so badly needed for treatment of resistant strains. Despite shorter half-lives and moderate oral bioavailability in comparison with DHA, two of the compounds of this series were able to cure malaria in mice at very low dosages, implicating extremely active metabolites. The optimum linker length for antimalarial activity was found to be a diaminoalkyl linker consisting of two carbon atoms, either unmethylated or bearing a single methyl group. / Thesis (PhD (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2013

Introduction - Malaria is a major global health problem, with more than 500 million reported cases and at least 1 million deaths each year. The main problem with malaria control is the emerging drug resistance. Plasmodium falciparum (P. falciparum) developed widespread resistance to antimalarial drugs such as chloroquine (CQ) and mefloquine, but not to the artemisinins. The World Health Organization (WHO) recommended artemisinin combination therapy (ACT) for the treatment of uncomplicated malaria in all chloroquine resistance areas. However, P. falciparum has recently started to display resistance to these ACTs, highlighting the need for new chemotherapeutic approaches for the treatment of P. falciparum infections. Aims - The aims of this study were: (i) to design and synthesise a new series of antimalarial hybrid drugs, consisting of dihydroartemisinin (DHA) and aminoquinoline moieties bound covalently through different, very distinctive linkers; (ii) to determine the in vitro antiplasmodial activity and cytotoxicity of the synthesised series; (iii) to ascertain whether the in vitro antiplasmodial activity of the promising compounds would be carried over in vivo against Plasmodium vinckei (P. vinckei); and, (iv) to obtain an indication of the pharmacokinetic properties of this class of antimalarial drugs by performing snapshot pharmacokinetic analysis. Methods - DHA was coupled via an aminoethylether bond to various aminoquinolines to give hybrids and hybrid-dimers. CQ-susceptible (D10 and 3D7) and CQ-resistant (Dd2) strains of P. falciparum were used to determine the in vitro antiplasmodial activity. In vitro cytotoxicity was assessed using a mammalian cell-line (Chinese Hamster Ovarian, CHO). The antiproliferative activity of the hybrid-dimers was tested against three cell lines; renal adenocarcinoma (TK-10), breast adenocarcinoma (MCF-7) and melanoma (UACC-62). P. vinckei-infected mice were treated with the hybrid drugs for four days at a dosage of 0.8 mg/kg, 2.5 mg/kg, 7.5 mg/kg or 15 mg/kg intraperitoneally (ip) or orally (po), with 2.7 mg/kg, 8.3 mg/kg, 25 mg/kg or 50 mg/kg, in order to determine their antimalarial activity. A snapshot oral and intravenous (IV) pharmacokinetic study was performed. Results - All compounds were obtained as the 10-β-isomers and were isolated as the oxalate salts. Low nanomolar in vitro antiplasmodial activities were displayed by several compounds in this series, with IC50 values ranging from 5.15 to 29.5 nM, in comparison with the values of 2.09–5.11 nM and 21.54–157.90 nM for each of DHA and CQ respectively. All compounds displayed good selectivity towards P. falciparum in vitro (selectivity index (SI) ≥ 20). Two of the hybrids, featuring non-methylated and methylated two-carbon diaminoalkyl linkers, exerted potent in vivo antimalarial activities, with ED50 values of 1.1 and 1.4 mg/kg by ip route and 12 and 16 mg/kg po, respectively. Long-term monitoring of parasitaemia showed a complete cure of mice (without recrudescence) at 15 mg/kg ip and at 50 mg/kg po for these two hybrids, whereas artesunate was able to provide a complete cure only at 30 mg/kg ip and 80 mg/kg po. Conclusions - These compounds may provide a lead into a new class of antimalarial drugs so badly needed for treatment of resistant strains. Despite shorter half-lives and moderate oral bioavailability in comparison with DHA, two of the compounds of this series were able to cure malaria in mice at very low dosages, implicating extremely active metabolites. The optimum linker length for antimalarial activity was found to be a diaminoalkyl linker consisting of two carbon atoms, either unmethylated or bearing a single methyl group. / Thesis (PhD (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2013

Utilizando a reação de acoplamento de Suzuki, novos polímeros e copolímeros semicondutores com elevado potencial para a fabricação de PLEDs foram sintetizados, tendo como finalidade unir em uma única camada emissiva, na forma de copolímeros ou na forma de blendas, materiais com propriedades transportadoras e injetoras de elétrons; grupos quinolina associados a materiais com elevadas propriedades de emissão de luz contendo grupos fluoreno. Esses copolímeros sintetizados, todos ainda não descritos na literatura ou em patentes, apresentaram rendimentos acima de 70% e rendimentos quânticos de fotoluminescência entre 60% e 83%, foram utilizados como camada emissiva na construção de PLEDs. Estes PLEDs foram caracterizados quanto ao seu comportamento elétrico através da obtenção de curvas de corrente em função da tensão (IxV) e dos espectros de eletroluminescência. Os resultados mostraram que a incorporação da quinolina aos copolímeros aumentou a sua estabilidade térmica, observada pela temperatura de inicio de degradação que elevou-se em até 80°C. Nos PLEDs, houve melhorias no balanceamento de cargas, dispensando até mesmo a deposição de uma camada adicional transportadora de elétrons (ETL). As tensões de operação desses dispositivos ficaram entre 2,0 e 5,2 V, com emissão entre 525 e 590nm. Esses materiais também tiveram as suas estruturas caracterizadas por ressonância magnética nuclear de hidrogênio, termogravimetria, calorimetria diferencial exploratória, espectroscopias no UV-Vis e no infravermelho, fluorimetria no UV-vis e cromatografia de permeação em gel. Filmes Langmuir e Langmuir- Blodgett dos copolímeros foram preparados e caracterizados por espectroscopia com luz polarizada de reflexão e absorção no infravermelho (PM-IRRAS) e por microscopia de força atômica (AFM). / New polymers and copolymers with a high potential for PLEDs constructions have been synthesized by Suzuki reaction and aims together in a single emissive layer in the form of copolymers or blended, materials with transporting and electron injection properties; quinoline groups linked to materials with high light emission properties as fluorene group. All these copolymers have not been described in literature or in patents, presented yields above 70%, quantum yields between 60% and 83% and were used as emissive layer in PLEDs. These PLEDs were characterized concerning their electrical behavior, by the characteristic J-V diode curves, and their electroluminescence. The results showed that the presence of quinoline increased its thermal stability at around 80° C and the PLEDs built with the synthesized copolymers do not need an extra ETL. The operating voltages of these devices were observed between 2.0 and 5.2 V with EL emission between 525 and 590nm. These new materials were also characterized by hydrogen nuclear magnetic resonance, thermogravimetry, differential scanning calorimetry, UV-Vis, Fluorescence and IR spectroscopy and gel permeation chromatography. Langmuir e Langmuir-Blodgett films were made and characterized by Polarization-Modulation Infrared Reflection-Absorption Spectroscopy (PM-IRRAS) and atomic force microscopy (AFM).

Visando o crescente interesse em pesquisa de novos materiais para a fabricação de dispositivos eletrônicos a base de polímeros semicondutores, com elevado potencial para a fabricação de diodos emissores de luz poliméricos os (PLEDs - Polymer light-emitting diodes), este presente trabalho teve como objetivo a síntese de novos copolímeros através da reação de acoplamento de Suzuki e a sua fabricação de PLEDs com esses novos materiais. É conhecido que um dos grandes problemas na fabricação desses dispositivos é propiciar um maior número de recombinações elétrons/ lacunas no interior de suas camadas ativas com a finalidade de aumentar a emissão de luz visivel. Para amenizar esse problema os copolímeros sintetizados tiveram como finalidade unir num único material, a propriedade de transporte de elétrons associada à boa emissão de luz. O objetivo final foi elevar a injeção de elétrons contribuindo para aumentar o número de recombinações dos pares elétrons/lacunas, resultando em aumento de eletroluminescência e de eficiência dos dispositivos. Os copolímeros inéditos foram sintetizados e caracterizados por ressonância magnética nuclear hidrogênio, termogravimetria, calorimetria diferencial exploratória, espectroscopia no UV-Vis e no infravermelho, fluorimetria no UV-vis, cromatografia de permeação em gel e voltametria cíclica. Os copolímeros foram também utilizados como camada ativa na construção de uma série de PLEDs com arquiteturas diferentes, tanto puro como em mistura com o poli(N-vinilcarbazol) (PVK), ou, ainda, utilizando tris-8-hidroxiquinolina alumínio (Alq3) como camada transportadora de elétrons ( ETL - Electron transport layer). Os dispositivos foram caracterizados quanto ao comportamento elétrico, pelas curvas de corrente por tensão (IxV), e à sua eletroluminescência. Os PLEDS fabricados com os copolímeros sintetizados mostraram que não necessitam do uso de uma camada transportadora de elétrons, ETLs, adicional. / Polymer light-emitting diodes (PLEDs) have been heavily researched since their initial fabrication and utilization. In order to improve the efficiency of polymeric light-emitting devices, new materials have been studied. This present study focuses in the preparation of new copolymers by Suzuki coupling reaction and then evaluate the copolymers as active layer in PLEDs. It is well known that the performance of PLEDs is still limited by the number of electron/hole recombination. To overcome this problem, a new material is proposed to integrate the functions of n charge carrier and light emission through copolymerization. Novel copolymers were synthesized and characterized by hydrogen nuclear magnetic resonance, thermogravimetry, and differential scanning calorimetry, UVVis, Fluorescence and IR spectroscopy, GPC and cyclic voltammetry. Copolymers thus prepared were used as active layer in a series of PLEDs with different architectures, pure and in blends with poly(N-vinylcarbazole) (PVK), as well as with tris-8 hydroxyquinoline aluminum (Alq3) as an extra electron transport layer. The devices were characterized concerning their electrical behavior, by the characteristic J-V diode curves, and their electroluminescence. It was demonstrated that the PLEDs built with the synthesized copolymers do not need an extra ETL.

Thesis submitted in fulfilment of the requirements for the Degree of Master's in Chemistry, Durban University of Technology, 2017. / Quinoline and its derivatives represent an important class of nitrogen-containing heterocylces as they are useful intermediates in organic synthesis and possess a broad spectrum of biological activities, such as anti-asthmatic, anti-inflammatory and anti-malarial activity. Hence, synthesis of novel compounds with potent biological activities is important in medicine. Significant research is directed into the development of new quinoline based structures and new methods for their preparations. In the past, synthesis of complex molecules was accomplished by step-wise reaction. This was time consuming and yield was generally low. Nowadays, multi-component reactions (MCRs) are being used since three or more substrates can be reacted in a one-pot reaction. Therefore yields are higher and the reaction is more efficient. In this research investigation novel quinoline derivatives, using the multi-component reaction protocol, were synthesized. After characterization of the product by several spectroscopic techniques, the biological potential of these compounds were assessed using lung cancer cell lines, bacteria and molecular modeling in an enzymatic system. In the synthetic part of this study, the first step was the preparation of the starting compound 2- chloro-3-formyl quinoline for which the Vilsmeier-Haack cyclisation protocol was used. The cyclisation was carried out by combining DMF and POCl3 at 5°C to form an electrophile which then reacted in situ with N-phenylacetamide at 100ºC to afford 2-chloro-3-formyl quinoline in high yield (95%). This was followed by the synthesis of a series of novel quinoline derivatives in a MCR system comprising 2- chloro-3-formyl quinoline, malononitrile, aromatic amines and dimethyl acetylenedicarboxylate in the presence of a catalytic amount of triethylamine. Valuable features of this routine included high yields, extensive substrate range and straight forward procedures. Eight novel poly-functionalised dihydropyridine quinoline derivatives were synthesized, purified and characterized. The outline for the synthesis of poly-functionalised dihydropyridine quinoline derivatives is presented graphically in Scheme 1. Scheme 2 shows the eight compounds synthesized and used subsequently for further studies. . Step 1 CH3 a N O H CHO N Cl Step 2 CHO CN N Cl CN NH2 R O OCH3 b OCH3 O MeO2C MeO2C N Cl CN N NH2 R = m-CH3, o-OCH3, p-Cl, m,p-Cl, o-F, m-F, p-F R Reaction Conditions: a. DMF, POCl3 b. Et3N, EtOH Scheme 1: Graphical representation for the synthesis of poly-functionalised dihydropyridine quinoline derivatives The novel eight compounds were screened for their potential activity in lung cancer cell lines. A549 cells were incubated for 24 hours with a range of concentrations of each compound, in triplicate, in a micro-titre plate together with an untreated control. Each experiment was conducted twice on separate occasions; the results from the first set matched the repeated experiment. The cells were then incubated (37ºC, 5% CO2) with the MTT substrate for 4 hours. Thereafter all supernatants were aspirated and DMSO was added to the wells. Finally the optical density was measured at 570 nm at a reference wavelength of 690 nm with an ELISA plate reader. The net MTT dependant absorbance (optical density) of each sample was calculated by subtracting the average absorbance of the blank from the average absorbance of each sample. Data were represented as mean optical density plus or minus the standard deviation. Four of the synthesized compounds (A1-A8) were evaluated for their cytotoxicity activities. The anti-cancer assay indicated that poly-functionalised dihydropyridine quinoline compounds, A2, A3 and A4 have good potential as anti-cancer drugs. Among them, A2 and A4 proved to be dose dependent with A4 having the highest toxicity at 250 µM and A8 having the highest toxicity at 125, 250 and 500 µM, whereas A1, A5, A6 and A7 were not cytotoxic. O H3CO H3CO O N Cl CN NH2 O H3CO H3CO O N Cl CN N NH2 OCH3 O H3CO H3CO O N Cl CN N NH2 O H3CO H3CO O N Cl CN NH2 CH3 Cl A1 A2 A3 A4 O H3CO H3CO O N Cl CN N NH2 F O H3CO H3CO O N Cl CN N NH2 O H3CO H3CO O N Cl CN NH2 O H3CO H3CO O N Cl CN N NH2 F Cl F Cl A5 A6 A7 A8 Scheme 2: Structures of novel poly-functionalised dihydropyridine quinoline derivatives by MCRs Since molecular docking is a key tool in structural molecular biology and computer-assisted drug design, these compounds were subjected to molecular docking and the binding mode for the compounds, within the active site of the protein, was analyzed. Docking of A1 to Human mdm2 protein provided insights into the binding regions. Three hydrogen bonds were formed between GLU 25 (2.7 Å distance), LEU 27 (3.2 Å distance) and LEU 54 (3.2 Å distance) atoms with binding energy of -8.91 kcal/mol. Docking of A1 with Human mdm2 indicated the lowest binding energy thereby showing strong affinity of the ligand molecule with the receptor which has been stabilized by strong hydrogen bond interactions in the binding pocket. This confirms that A1 is a better inhibitor for E3 ubiquitin-protein ligase mdm2 than all the other compounds tested (A2-A8). Further, the eight novel poly-functionalised dihydropyridine quinoline derivatives were evaluated for their antibacterial activity. This was performed using the MABA method against three strains i.e. Gram negative; Pseudomonas aeruginosa (ATCC 27853), Escherichia coli (ATCC 25922) and Gram positive; Staphylococcus aureus (ATCC 29213) using the broth micro dilution method. Standard antibiotics (ciprofloxacin and nalidixic acid) were used as positive controls and DMSO was used as a negative control. The results obtained from the anti-bacterial assay showed that compounds A4, A7 and A8 have high activity, whereas A2 and A3 showed poor activity against all the tested bacterial strains. Compound A6 showed no activity against S. aureus and E. coli. / M

The ability of derivatives of 2-aminotetralins (2AT), cis- or trans-isomers of octahydrobenzo[f]quinolines (BfQ) and clonidine to modulate acetylcholine release was studied using field-stimulated guinea pig ilea (GPI). Antihistaminic and antiacetylcholine activities were also determined using isolated superfused segments of GPI. Hydroxylated 2AT, BfQ and clonidine inhibited field stimulation-induced contractions through α-adrenoceptor mechanisms which were antagonized by phentolamine. In contrast, the inhibition produced by nonhydroxylated 2AT was not attenuated by α-adrenoceptor antagonism. 2AT, trans-7,8-dihydro-BfQ and cis-8,9-dihydroxy-BfQ inhibited contractions induced by nicotine bitartrate using superfused GPI. Clonidine was inactive as an antinicotinic agent and there was no correlation between a compound's ability to inhibit contractions induced by field stimulation and its antinicotinic activity. Various 2AT derivatives demonstrated weak antimuscarinic and/or antihistaminic activities on superfused ileal segments. These data demonstrate that these agents posses a spectrum of pharmacological activity.

The decomposition mechanisms of various coal constituents undergoing pyrolysis are of great concern in environmental circles (especially those coal constituents containing nitrogen). Most methods of burning coal that are efficient involve doing so at high temperatures. This invariably results in a large portion of non-combusting coal being heated to high temperatures also causing pyrolysis of the original coal constituents. The end result of such pyrolysis is the production of a number of noxious gaseous products. If we are to design methods of reducing the amount of toxins that are produced from the industrial use of coal, it is necessary to understand the pyrolysis process mechanistically. Due to the great number of coal constituents, a reasonable approach to such a mechanistic study is to use a simpler model. Pyridine makes an excellent starting model upon which to build. Our study focuses on interpretation of proposed reaction channels from experimental work on pyridine, quinoline and isoquinoline shock-tube decomposition in light of new ab initio energy calculations using Gaussian 98. The pathways thus determined support the proposed pyrolysis mechanisms and agree with experimental evidence obtained from independent groups of researchers performing shock tube pyrolysis.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 1980 / Vita. / Bibliography: leaves 269-273. / by Selahattin Gültekin. / Ph. D. / Ph. D. Massachusetts Institute of Technology, Department of Chemical Engineering

The mass spectra of some monomethylquinolines, dimethylquinolines, monoethylquinolines and monopropylquinolines have been determined. In addition, the spectra of 1,2,3,4-tetrahydroquinoline, 5,6,7,8-tetrahydroquinoline and some monomethyl-1,2,3,4-tetrahydroquinolines have also been studied. Fragmentation mechanisms are proposed to account for the most important peaks in the spectra of these compounds. Deuterium labelled analogues of many of the compounds have been prepared and their spectra support the proposed fragmentation mechanisms. / Thesis / Doctor of Philosophy (PhD)

Le développement de radiotraceurs (18F) des récepteurs de la sérotonine 5-HT6 et 5-HT7 pour l'imagerie TEP (tomographie par émission de positons) permettrait d'étudier la fonction et l'implication de ces récepteurs dans des maladies neurodégénératives telles que la schizophrénie ou la maladie d'Alzheimer. A partir des structures et pharmacophores déjà décrits dans la littérature, nous nous sommes orientés vers des dérivés pyrrolidiniques pour les récepteurs 5-HT7 et quinolines pour les récepteurs 5-HT6. 7 radioligands des récepteurs 5-HT7 marqués au fluor 18 ont pu être étudiés par autoradiographie et imagerie μTEP sur le rat et ont montrés des fixations intéressantes, mais avec une sélectivité moyenne du récepteur. 16 ligands du récepteur 5-HT6 ont été synthétisés et 4 d'entre eux ont été radiomarqués afin d'identifier le 2FNQ1P comme radioligand sélectif vis-à-vis du récepteur 5-HT2A (principal récepteur en compétition). Les premières images TEP réalisées sur le chat ont montrées un marquage sélectif dans les zones cérébrales riches en 5-HT6. La poursuite des études biologiques menées en collaboration avec le CERMEP – Imagerie du vivant permettront d'approfondir les caractéristiques de ces nouveaux radioligands synthétisés / Development of fluorine 18 labeled radiotracer of 5-HT6 and 5-HT7 receptors for PET imaging (positron emission tomography) allows the study of those receptors in various neurodegenerative diseases such as schizophrenia and Alzheimer disease. Description of structures and pharmacophores in literature led to pyrrolidine derivatives for 5-HT7 receptors and quinolones for 5-HT6. After their synthesis, 7 radioligands of 5-HT7 receptors have been studied by autoradiography and μPET. These radioligands have shown interesting binding on rat, with more or less selectivity for the receptor. 14 ligands of 5-HT6 receptors have been synthesized and 4 have been radiolabeled to select 2FNQ1P as a selective radioligand toward 5-HT2A. First PET images on cat have shown a selective binding in 5- HT6 rich area in brain. Pursue of biological studies, in collaboration with CERMEP – Imagerie du vivant will give more information on those new radioligands