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dc.contributor.advisorMalan, S.F.
dc.contributor.advisorOliver, D.W.
dc.contributor.advisorCarpy, A.J.M.
dc.contributor.authorVan Zyl, Sandra
dc.date.accessioned2009-02-11T13:35:38Z
dc.date.available2009-02-11T13:35:38Z
dc.date.issued2004
dc.identifier.urihttp://hdl.handle.net/10394/526
dc.descriptionThesis (M.Sc. (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2005.
dc.description.abstractThe acquired immunodeficiency syndrome (AIDS) pandemic continuous to be a medical, social and economic challenge of staggering proportions. The human immunodeficiency virus (HIV) has been identified as the etiologic agent of this disease. The HIV-1 protease enzyme is one of the specific targets for anti-retroviral therapy. It was chosen for this study because of its well described crystal structure and based on previous research and results. A novel series of protease inhibitors were designed, and evaluated for possible anti-HIV activity. 1,3-Diaminopropan-2-01 derivatives containing benzofuran-2-carboxylic acid/-aldehyde and indole-2-carboxylic acid/-aldehyde moieties were included in this study and evaluated for possible protease interaction. A structure search performed on compounds containing the core structure 1,3-diaminopropan-2-01 guided the selection of the published structure, (S,S,R)-1-[2- (N-t-Butoxycarbonyl)amino-1 -benzyl-2-hydroxypropyl]-N-methyl-N-benzylaminobenzoylimide (AQ148) or 3AID (PDB ID) of the Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank (PDB). The premise for this study was that the novel series is structurally similar to AQ148, containing the hydroxyethylamine isostere, with affinity for the HIV protease enzyme. Molecular modelling was performed using a SGI Fuel computer, with Insight II software to determine the feasibility for further evaluation of candidate compounds. Root mean square (RMS) fitting values were obtained by superimposing the proposed compounds on AQ148. The results of this RMS fit of candidate compounds on AQ148 indicated the likelihood of interaction of the proposed compounds at the protease active site. The hydrogen bond network formed in the enzyme was also used as an indication for possible inhibitory activity. H-bonds from the substrate to residues of the active site in the enzyme, Asp 25 and Asp '25 as well as H-bonds to the water molecule, which is bound to the flap residues, lle 50 and lle '50 was taken as essential interactions. The molecular modelling study indicated that the novel compounds were reasonable candidates for further investigation in view of their interaction profiles at the HIV protease active site. Compounds were synthesised by using either direct coupling or activation chemistry. Direct coupling of 1,3-diaminopropan-2-01 with benzofuran-2-carboxaldehyde and indole-3- carboxaldehyde was done respectively. Activation chemistry, using N,N’-carbonyldiimidazole (CDI) was used to synthesise the other compounds. Difficulties were experienced with the yields, purification and isolation of the compounds due to solubility properties and multiple reactions taking place. Selected, compounds were included in the biological evaluation against HIV-1. The pure compounds namely SVZ-2 and 4 were evaluated by measuring T-cell line adapted HIV-1 strain neutralisation in MT-2 cells. MN and llB virus strains were used in this study, as well as a positive control, IBU21 (a sample isolated from an HIV-I infected individual with neutralising activity). The biological evaluation showed no meaningful inhibition by the novel compounds, but was of experimental value in this kind of study/research. The insolubility of the compounds in aqueous solutions could have reduced their bioavailability, which in turn would account for their lack of inhibitory activity. This study prompts further investigation into small substituted molecules for HIV-1 protease inhibition. This first exploration into the possible anti-HIV properties of this series could thus pave the way for further in depth anti-HIV studies on this class of compounds and derivatives thereof.
dc.publisherNorth-West University
dc.titleEvaluation of N,N'-disubstituted 1,3-Diaminopropan-2-ols for anti-HIV activityen
dc.typeThesisen
dc.description.thesistypeMasters


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