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dc.contributor.advisorN'Da, D.D.
dc.contributor.advisorCloete, T.T.
dc.contributor.authorVan Heerden, Lezanne
dc.date.accessioned2013-05-09T08:53:03Z
dc.date.available2013-05-09T08:53:03Z
dc.date.issued2012
dc.identifier.urihttp://hdl.handle.net/10394/8518
dc.descriptionThesis (MSc (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2012
dc.description.abstractEvery year an estimated 1 million people die of malaria, with the majority of these deaths reported in Africa. The disease caused by Plasmodium falciparum affects an approximate 250 million people annually and with the emergence of monodrug and multidrug resistance it has seen resurgence in the last decade. The decline in effectiveness of chloroquine in the treatment of drug resistant malaria has contributed to the doubling of malaria specific mortality in the last fifteen years. Since the quinoline drug family represents the basis of malaria chemotherapy for much of the past 50 years. This spread of resistance to existing antimalarial drugs such as chloroquine, mefloquine, sulfadoxine and pyrimethamine has driven the search for new drugs that might circumvent parasite resistance mechanisms. The mechanism of chloroquine resistance is associated with reduced accumulation of the drug inside the digestive vacuole, which is connected to a Plasmodium falciparum chloroquine resistance transporter (PfCRT) or ATP-dependant P-glycoprotein efflux pump (Pgh1). The PfCRT protein demonstrates a structural specificity for the chloroquine side chain, which allows for changes in the structures of drugs to have different affinities for the transporter. New drugs with structural modifications that result in reduced affinity for PfCRT may be able to avoid reduced drug accumulation. Despite resistance, the aminoquinoline pharmacophore remains an attractive scaffold in the design of new drugs, since it demonstrates a unique affinity for haematin. This is a desirable feature since the quinoline antimalarial drugs inhibit conversion of haematin to hemozoin. The 4-aminoquinoline antimalarial drugs are also weak bases which traverse down the pH gradient to concentrate inside the acidic food vacuole. The protonation of these drugs inside the vacuole makes them membrane impermeable and increases their accumulation, which allows for the high concentrations required for hemozoin inhibition. The aim of this study was to synthesise a series of bisquinoline and bispyrrolo[1,2a]quinoxaline compounds containing various polyamines, which may act as potential protonation sites in the hope of increasing their accumulation via pH-trapping. In order to achieve this aim twelve bisquinolines 4 - 15 and five bispyrrolo[1,2a]quinoxalines 16 - 20 were synthesised and their structures confirmed by nuclear magnetic resonance spectroscopy (NMR) and mass spectroscopy (MS). The aqueous solubility (Sw) and distribution coefficients (logD) were experimentally determined in phosphate buffered saline (pH 5.5) to mimic the parasitic digestive vacuole environment. The compounds were screened for antimalarial activity alongside chloroquine (CQ) against chloroquine-sensitive (CQS) D10 and the moderately chloroquine-resistant (CQR) Dd2 strains of P. falciparum. The series were also tested for cytotoxicity against Chinese Hamster Ovarian (CHO) cells, using emetine as reference drug. The most active compounds against P. falciparum were screened for anticancer activity against the TK10 (renal), UACC62 (melanoma) and MCF7 (breast) cancer cells. The bisquinoline- and bispyrrolo[1,2a]quinoxaline compounds were found to be more hydrophilic than chloroquine (SW = 0.033 mM) itself with aqueous solubility varying in the 18.94 - 38.86 mM range. Irrespective of the series, the aqueous solubility increases with the increase in potential protonation sites (N atoms) in the polyamine bridge. However, this effect is overruled if the carbon-carbon chain separating two nitrogen atoms in the polyamine also increases. The in vitro data revealed seven of the twelve bisquinoline compounds to be significantly more potent against the CQR (Dd2) strain compared to chloroquine. Compounds 8 (7- chloro-4-[10-(7-chloroquinolin-4-yl)-1,4,7,10-tetraazadecan-1-yl]quinoline) (IC50 = 35.49 nM) and 9 (7-chloro-4-[12-(7-chloroquinolin-4-yl)-1,5,8,12-tetraazadodecan-1-yl]quinoline) (IC50 = 49.48 nM) featuring the triethylenetetramine or N,N’-bis(3-aminopropyl)ethylenediamine linkers respectively, were the most active of all synthesised compounds. They were found significantly more potent than CQ (IC50 = 242.3 nM) against the Dd2 strain. However, they were as potent as CQ (IC50 = 48.35 nM) against the D10 strain. This potent activity against the CQR strain could possibly be as result of enhanced pH-trapping inside the digestive vacuole, since they contain increased protonation sites that also enhance their hydrophilicity. These compounds also displayed the best drug profile based on toxicity and antimalarial activity, both demonstrating good selectivity towards parasitic cells with a selectivity index of greater than 90. The bis-(7-chloroquinoline)-series displayed the most potent antimalarial activity and were subsequently screened for potential anticancer activity. The series showed potent growth inhibitory activity against all 3 cancer cell lines. Presumably the polyamine bridges of bisquinoline compounds provide increased ionisation of structures that allows for increased van der Waals interactions with the highly polar phosphate backbone of the parasite DNA. These interactions possibly interfere with cell replication and cause DNA strand scission, since bisquinolines are known to bind by external attachment to the AT-rich sequences of DNA, which is less stable and easier to pull apart. Compound 4 (7-chloro-N-[2-({2-[(7-chloroquinolin-4-yl)amino]ethyl}amino)ethyl]quinolin-4-amine), 6 (7-chloro-N-[3-({3-[(7- chloroquinolin-4-yl)amino]propyl}amino)propyl]quinolin-4-amine) and 7 (bis({3-[(7- chloroquinolin-4-yl)amino]propyl})(methyl)amine) showed significantly more potent growth inhibition efficacy against breast (MCF7) cancer cells compared to etoposide (TGI > 100 μM) with TGI-values in the range of 0.55 - 0.69 μM. Compounds 4, 6 and 7 were also the most potent against TK10 (renal) and melanoma (UACC62) cancer cells with TGI-values of 0.6, 2.05 and 1 μM against TK10 cells respectively, compared to etoposide (TGI = 43.33 μM). Against melanoma cells the TGI values were 0.59 for 4, 0.74 for 6 and 0.64 μM for 7, compared to 4 μM for etoposide. The results reveal that a two C-C chain, and a three C-C chain with or without methyl substitution is the optimal linker to separate the identical nonintercalating pharmacophores for potent anticancer activity. All of the compounds in the series warrant further investigation in search of more potent anticancer agents.en_US
dc.language.isoenen_US
dc.publisherNorth-West University
dc.titleSynthesis and in vitro antimalarial activity of series of bisquinoline and bispyrrolo[1,2a]quinoxaline compoundsen
dc.typeThesisen_US
dc.description.thesistypeMastersen_US


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