Parkinson’s disease (PD) is an age-related neurodegenerative disorder. The degeneration of the neurons of the substantia nigra in the midbrain leads to the loss of dopamine from the striatum, which is responsible for the motor symptoms of PD. In the brain, the enzyme, monoamine oxidase B (MAOB), An analysis of the Lineweaver-Burk plots indicated that 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)- quinolinone inhibits MAO-B with a Ki value of 2.7 nM. An analysis of the structure-activity relationships for MAO-B inhibition shows that substitution on the C7 position of the 3,4-dihydro- 2(1H)-quinolinone moiety leads to significantly more potent inhibition compared to substitution on C6. In this regard, a benzyloxy substituent on C7 is more favourable than phenylethoxy and phenylpropoxy substitution on this position. In spite of this, C6-substituted 3,4-dihydro-2(1H)-quinolinone with potent MAO-B inhibitory activities were also identified. An analyses of selected properties of the 3,4-dihydro-2(1H)- quinolinones showed that the compounds are highly lipophilic with logP values in the range of 3.03- 4.55. LogP values between 1 and 3 are, however, in the ideal range for bioavailability. The compounds synthesised have logP values higher than 3, which may lead to lower bioavailability. Laboratory data further showed that none of the 3,4-dihydro-2(1H)-quinolinones are highly toxic to cultured cells at the concentrations, 1 μM and 10 μM, tested. For example, the most potent MAO-B inhibitor, 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)-quinolinone, reduced cell viability to 88.11% and 86.10% at concentrations of 1 μM and 10 μM, respectively. These concentrations are well above its IC50 value for the inhibition of MAO-B. At concentrations required for MAO-B inhibition, the more potent 3,4-dihydro-2(1H)-quinolinones are thus unlikely to be cytotoxic. It may thus be concluded that C7-substituted 3,4-dihydro-2(1H)-quinolinones are promising highly potent and selective MAO-B inhibitors, and thus leads for the therapy of Parkinson’s disease. represents a major catabolic pathway of dopamine. Inhibitors of MAO-B conserve the depleted supply of dopamine and are thus used in the therapy of PD. In the present study, a series of 3,4- dihydro-2(1H)-quinolinone derivatives were synthesized and evaluated as inhibitors of recombinant human MAO-A and MAO-B. These quinolinone derivatives are structurally related to a series of coumarin (1-benzopyran-2-one) derivatives, which has been reported to act as MAO-B inhibitors. C6- and C7-substituted 3,4-dihydro-2(1H)-quinolinone derivatives were synthesized by reacting 6- or 7- hydroxy-3,4-dihydro-2(1H)-quinolinone with an appropriately substituted alkyl bromide in the presence of base. To evaluate the MAO inhibitory properties (IC50 values) of the quinolinone derivatives the recombinant human MAO-A and MAO-B enzymes were used. The reversibility of inhibition of a representative 3,4-dihydro-2(1H)-quinolinone derivative was examined by measuring the recovery of enzyme activity after the dilution of the enzyme-inhibitor complexes, while the mode of MAO inhibition was determined by constructing Lineweaver-Burk plots. To determine the lipophilicity of the 3,4-dihydro-2(1H)-quinolinone derivatives, the logP values were measured. The toxicity of the 3,4-dihydro-2(1H)-quinolinone derivatives towards cultured cells (cytotoxicity) was also measured. The results document that the 3,4-dihydro-2(1H)-quinolinone derivatives are highly potent and selective MAO-B inhibitors with most homologues exhibiting IC50 values in the nanomolar range. The most potent MAO-B inhibitor, 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)-quinolinone, exhibits an IC50 value of 2.9 nM with a 2750-fold selectivity for MAO-B over the MAO-A isoform. As a MAO-B inhibitor, this compound is approximately equipotent to the most potent coumarin derivative (IC50 = 1.14 nM) reported in literature. Since MAO-B activity could be recovered after dilution of enzyme-inhibitor mixtures, it may be concluded that 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)- quinolinone is a reversible MAO-B inhibitor. The Lineweaver-Burk plots constructed for the inhibition of MAO-B by 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)-quinolinone were linear and intersected on the y-axis. These data indicated that this compound also is a competitive MAO-B inhibitor. / MSc (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2014

Parkinson’s disease (PD) is an age-related neurodegenerative disorder. The degeneration of the neurons of the substantia nigra in the midbrain leads to the loss of dopamine from the striatum, which is responsible for the motor symptoms of PD. In the brain, the enzyme, monoamine oxidase B (MAOB), An analysis of the Lineweaver-Burk plots indicated that 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)- quinolinone inhibits MAO-B with a Ki value of 2.7 nM. An analysis of the structure-activity relationships for MAO-B inhibition shows that substitution on the C7 position of the 3,4-dihydro- 2(1H)-quinolinone moiety leads to significantly more potent inhibition compared to substitution on C6. In this regard, a benzyloxy substituent on C7 is more favourable than phenylethoxy and phenylpropoxy substitution on this position. In spite of this, C6-substituted 3,4-dihydro-2(1H)-quinolinone with potent MAO-B inhibitory activities were also identified. An analyses of selected properties of the 3,4-dihydro-2(1H)- quinolinones showed that the compounds are highly lipophilic with logP values in the range of 3.03- 4.55. LogP values between 1 and 3 are, however, in the ideal range for bioavailability. The compounds synthesised have logP values higher than 3, which may lead to lower bioavailability. Laboratory data further showed that none of the 3,4-dihydro-2(1H)-quinolinones are highly toxic to cultured cells at the concentrations, 1 μM and 10 μM, tested. For example, the most potent MAO-B inhibitor, 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)-quinolinone, reduced cell viability to 88.11% and 86.10% at concentrations of 1 μM and 10 μM, respectively. These concentrations are well above its IC50 value for the inhibition of MAO-B. At concentrations required for MAO-B inhibition, the more potent 3,4-dihydro-2(1H)-quinolinones are thus unlikely to be cytotoxic. It may thus be concluded that C7-substituted 3,4-dihydro-2(1H)-quinolinones are promising highly potent and selective MAO-B inhibitors, and thus leads for the therapy of Parkinson’s disease. represents a major catabolic pathway of dopamine. Inhibitors of MAO-B conserve the depleted supply of dopamine and are thus used in the therapy of PD. In the present study, a series of 3,4- dihydro-2(1H)-quinolinone derivatives were synthesized and evaluated as inhibitors of recombinant human MAO-A and MAO-B. These quinolinone derivatives are structurally related to a series of coumarin (1-benzopyran-2-one) derivatives, which has been reported to act as MAO-B inhibitors. C6- and C7-substituted 3,4-dihydro-2(1H)-quinolinone derivatives were synthesized by reacting 6- or 7- hydroxy-3,4-dihydro-2(1H)-quinolinone with an appropriately substituted alkyl bromide in the presence of base. To evaluate the MAO inhibitory properties (IC50 values) of the quinolinone derivatives the recombinant human MAO-A and MAO-B enzymes were used. The reversibility of inhibition of a representative 3,4-dihydro-2(1H)-quinolinone derivative was examined by measuring the recovery of enzyme activity after the dilution of the enzyme-inhibitor complexes, while the mode of MAO inhibition was determined by constructing Lineweaver-Burk plots. To determine the lipophilicity of the 3,4-dihydro-2(1H)-quinolinone derivatives, the logP values were measured. The toxicity of the 3,4-dihydro-2(1H)-quinolinone derivatives towards cultured cells (cytotoxicity) was also measured. The results document that the 3,4-dihydro-2(1H)-quinolinone derivatives are highly potent and selective MAO-B inhibitors with most homologues exhibiting IC50 values in the nanomolar range. The most potent MAO-B inhibitor, 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)-quinolinone, exhibits an IC50 value of 2.9 nM with a 2750-fold selectivity for MAO-B over the MAO-A isoform. As a MAO-B inhibitor, this compound is approximately equipotent to the most potent coumarin derivative (IC50 = 1.14 nM) reported in literature. Since MAO-B activity could be recovered after dilution of enzyme-inhibitor mixtures, it may be concluded that 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)- quinolinone is a reversible MAO-B inhibitor. The Lineweaver-Burk plots constructed for the inhibition of MAO-B by 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)-quinolinone were linear and intersected on the y-axis. These data indicated that this compound also is a competitive MAO-B inhibitor. / MSc (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2014

Nitrogen trifluoride (NF3) is frequently used as a source of fluorine in the electronics device manufacturing industry as a dry etchant during plasma assisted etching of silicon wafers, or during the plasma cleaning of chemical vapor deposition chambers. As a result of the electrochemical synthesis procedures in which carbon anodes are used in a fluorine-rich environment, NF3 product streams are frequently contaminated with ppm-amounts of carbon tetrafluoride (CF4). The electronics manufacturing industry, however, requires NF3 of exceptional purity, i.e. so-called VLSI-grade (very large scale integration) NF3, with CF4 concentrations of 20 ppm and below. Due to the close chemical and physical similarities of the two compounds, the removal of CF4 from NF3 has proven to be rather difficult, and current NF3 purification technologies are relatively inefficient. Although membrane gas separation has proven to be competitive in terms of operating costs and energy efficiency, its use for the purification of NF3 seems to have remained unexplored to date. In this study, the use of high free volume glassy perfluoropolymers of Teflon AF2400, Teflon AF1600, and Hyflon AD60 was therefore investigated. To be able to measure the pure and mixed gas permeabilities and selectivities of the solution-cast membranes towards NF3 and CF4, a custom built experimental setup was used, in which a newly developed gas chromatographic (GC) analysis method was implemented. Using divinylbenzene-styrene co-polymer stationary phases in the form of Super Q, a reliable quantification of mixtures of NF3 and CF4 were achieved without requiring additional fluorocarbon liquid stationary phases, as is commonly used in NF3 production environments. Furthermore, by implementing a dual-channel configuration it was possible to quantify a wide range of NF3 and CF4 concentrations. Using the newly developed technique, NF3 and CF4 concentrations of ca. 1 mol% and upwards could be quantified using a Thermal Conductivity Detector (TCD) on one channel, and NF3 and CF4 concentrations of between ca. 40 vppm and 4000 vppm could be measured using a Pulsed Discharge Helium Ionisation Detector (PDHID) on the second channel of the GC method. The glassy perfluoropolymer membranes of Teflon AF2400, Teflon AF1600, and Hyflon AD60 were prepared by a solution casting method, and it was found that annealing at sufficiently high temperatures (170 – 200 °C) ensured optimum permeability selectivity. In contrast, thermal analysis of the solution-cast Hyflon AD60 membranes that were heated to only 95 °C confirmed that the polymer matrix was significantly swollen due to a residual amount of the casting solvent. Consequently, considerably reduced selectivity and increased permeability of both NF3 and CF4 were observed for such solvent-swollen Hyflon AD60 membranes in comparison with the non-swollen membranes that were annealed at 170 °C. Nonetheless, the measured He/N2 permeability and permeability selectivity of all the membranes studied compared favourably with literature values, and selectively permeated NF3 rather than CF4 wherein the pure and mixed gas permeability selectivity displayed a clear dependence on the fractional free volume (FFV) of the polymer matrices. Thus, in accordance with the decreasing FFV of the perfluoropolymers in the order Teflon AF2400 > Teflon AF1600 > Hyflon AD60, the NF3 permeability decreased from 227 Barrer for Teflon AF2400, to 29 Barrer for Teflon AF1600, to 1.9 Barrer for Hyflon AD60. In contrast, the NF3/CF4 selectivity, α(NF3/CF4), increased inversely from 4.5 for Teflon AF2400, to 6.0 for Teflon AF1600, to the highest selectivity of 12 which was obtained using Hyflon AD60. To elucidate the mechanism of separation, the transport properties of NF3 and CF4 in Teflon AF2400 and Teflon AF1600 w.r.t. diffusion and solubility were studied using Molecular Dynamics (MD), Grand Canonical Monte Carlo (GCMC), and statistical thermodynamic techniques. The results indicated that NF3/CF4 diffusion selectivity (DNF3/DCF4) was favoured by the lower free volume of Teflon AF1600, whereas poor correlation was achieved between the GCMC calculated sorption isotherms of CF4 and the experimentally determined isotherms as reported in the literature. Consequently, the non-equilibrium lattice fluid (NELF) model, which more accurately described the sorption isotherms of CF4, was used to evaluate the solubility selectivity. It was found that by adjusting the NELF model interaction parameter, Ψ, favourable NF3/CF4 solubility selectivities (SNF3/SCF4) were predicted. Furthermore, by combining the solubility selectivity values with the diffusion selectivities calculated from the MD results, permeability selectivity predictions that correlated well with the experimentally determined values were obtained. Based on a semi-quantitative technological evaluation, it was concluded that although good NF3/CF4 mixed gas permeability selectivity was obtained with Hyflon AD60, further research into improving the NF3 solubility, and hence permeability will aid in the development of an efficient membrane gas separation process for the purification of NF3. / PhD (Chemistry),North-West University, Potchefstroom Campus, 2013.

Nitrogen trifluoride (NF3) is frequently used as a source of fluorine in the electronics device manufacturing industry as a dry etchant during plasma assisted etching of silicon wafers, or during the plasma cleaning of chemical vapor deposition chambers. As a result of the electrochemical synthesis procedures in which carbon anodes are used in a fluorine-rich environment, NF3 product streams are frequently contaminated with ppm-amounts of carbon tetrafluoride (CF4). The electronics manufacturing industry, however, requires NF3 of exceptional purity, i.e. so-called VLSI-grade (very large scale integration) NF3, with CF4 concentrations of 20 ppm and below. Due to the close chemical and physical similarities of the two compounds, the removal of CF4 from NF3 has proven to be rather difficult, and current NF3 purification technologies are relatively inefficient. Although membrane gas separation has proven to be competitive in terms of operating costs and energy efficiency, its use for the purification of NF3 seems to have remained unexplored to date. In this study, the use of high free volume glassy perfluoropolymers of Teflon AF2400, Teflon AF1600, and Hyflon AD60 was therefore investigated. To be able to measure the pure and mixed gas permeabilities and selectivities of the solution-cast membranes towards NF3 and CF4, a custom built experimental setup was used, in which a newly developed gas chromatographic (GC) analysis method was implemented. Using divinylbenzene-styrene co-polymer stationary phases in the form of Super Q, a reliable quantification of mixtures of NF3 and CF4 were achieved without requiring additional fluorocarbon liquid stationary phases, as is commonly used in NF3 production environments. Furthermore, by implementing a dual-channel configuration it was possible to quantify a wide range of NF3 and CF4 concentrations. Using the newly developed technique, NF3 and CF4 concentrations of ca. 1 mol% and upwards could be quantified using a Thermal Conductivity Detector (TCD) on one channel, and NF3 and CF4 concentrations of between ca. 40 vppm and 4000 vppm could be measured using a Pulsed Discharge Helium Ionisation Detector (PDHID) on the second channel of the GC method. The glassy perfluoropolymer membranes of Teflon AF2400, Teflon AF1600, and Hyflon AD60 were prepared by a solution casting method, and it was found that annealing at sufficiently high temperatures (170 – 200 °C) ensured optimum permeability selectivity. In contrast, thermal analysis of the solution-cast Hyflon AD60 membranes that were heated to only 95 °C confirmed that the polymer matrix was significantly swollen due to a residual amount of the casting solvent. Consequently, considerably reduced selectivity and increased permeability of both NF3 and CF4 were observed for such solvent-swollen Hyflon AD60 membranes in comparison with the non-swollen membranes that were annealed at 170 °C. Nonetheless, the measured He/N2 permeability and permeability selectivity of all the membranes studied compared favourably with literature values, and selectively permeated NF3 rather than CF4 wherein the pure and mixed gas permeability selectivity displayed a clear dependence on the fractional free volume (FFV) of the polymer matrices. Thus, in accordance with the decreasing FFV of the perfluoropolymers in the order Teflon AF2400 > Teflon AF1600 > Hyflon AD60, the NF3 permeability decreased from 227 Barrer for Teflon AF2400, to 29 Barrer for Teflon AF1600, to 1.9 Barrer for Hyflon AD60. In contrast, the NF3/CF4 selectivity, α(NF3/CF4), increased inversely from 4.5 for Teflon AF2400, to 6.0 for Teflon AF1600, to the highest selectivity of 12 which was obtained using Hyflon AD60. To elucidate the mechanism of separation, the transport properties of NF3 and CF4 in Teflon AF2400 and Teflon AF1600 w.r.t. diffusion and solubility were studied using Molecular Dynamics (MD), Grand Canonical Monte Carlo (GCMC), and statistical thermodynamic techniques. The results indicated that NF3/CF4 diffusion selectivity (DNF3/DCF4) was favoured by the lower free volume of Teflon AF1600, whereas poor correlation was achieved between the GCMC calculated sorption isotherms of CF4 and the experimentally determined isotherms as reported in the literature. Consequently, the non-equilibrium lattice fluid (NELF) model, which more accurately described the sorption isotherms of CF4, was used to evaluate the solubility selectivity. It was found that by adjusting the NELF model interaction parameter, Ψ, favourable NF3/CF4 solubility selectivities (SNF3/SCF4) were predicted. Furthermore, by combining the solubility selectivity values with the diffusion selectivities calculated from the MD results, permeability selectivity predictions that correlated well with the experimentally determined values were obtained. Based on a semi-quantitative technological evaluation, it was concluded that although good NF3/CF4 mixed gas permeability selectivity was obtained with Hyflon AD60, further research into improving the NF3 solubility, and hence permeability will aid in the development of an efficient membrane gas separation process for the purification of NF3. / PhD (Chemistry),North-West University, Potchefstroom Campus, 2013.