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Thesis (M.Sc. (Chemistry)) -- University of Limpopo, 2021 / Breast cancer is a malignant tumour that starts in the cells of the breast. Many studies revealed aromatase (CYP19A1) and cyclin-dependent kinase 2 (CDK2) as possible therapeutic targets regarding breast cancer treatment, because they play crucial roles in anti-apoptotic processes during cell proliferation. Quinoxaline derivatives have attracted a great deal of attention due to their biological activities against fungi, virus, bacteria and cancer. Computer modelling was employed in order to reduce time and cost by searching the library of molecules and identifying those which are likely to bind to the drug target. A library of new one hundred (100) nitro and amino quinoxaline alkyne derivatives were successfully designed and screened against target proteins (CYP19A1 and CDK2) using virtual screening technique and thirteen (13) molecules were identified to be hit compounds against both targets with the docking score ranging from -6.143 to -8.372 kcal/mol as a measure of binding affinity. The hit compounds were subjected to IFD in order to identify tight binding through intermolecular interactions with active site residues of the binding pocket of the target proteins. All identified nitro and amino quinoxaline alkyne derivatives were successfully synthesised in a multi-step reaction sequence and their spectroscopic analysis (NMR, FTIR and MS) were in good agreement with the proposed structures in a good to moderate yield. The newly synthesised novel amino and nitro-quinoxaline derivatives were evaluated for anti-proliferative activity against breast cancer (MCF-7). Compound 59 showed to possess good inhibition against MCF-7 with an IC50 of 9.102 μM, whereas compounds 34, 54, 56 and 61 showed promising activity against MCF-7 with an IC50 value of < 50 μM. However, the MTT assay results showed that 59 was found to be toxic with an IC50 value of 0.205 μM against Raw 264.7 cell line. The dose response investigations showed that 31 and 34 have the promising anti-cancer activity against CYP19A and the correlation between molecular modelling (in-silico) and CYP19A inhibition activities (in- vitro), was established as compounds 31 and 34 were identified to bind to the drug target (CYP19A) with the docking score of -8.372 and 7.630 kcal/mol respectively. All the synthesized compounds were evaluated for the antitubercular activity against Mtb H37Rv strain as a secondary study. Compounds 57-62 with nitro-quinoxaline derivatives exhibited stronger inhibitory effects on Mtb H37Rv strain. In addition, compounds 60 and 62 were found to be most active against Mtb H37Rv with the high activity at MIC90 of <0.65 and <0.64 μM respectively. All active compounds are currently investigated for their cytotoxicity which have not been investigated before. / National Research Foundation (NRF) and Sasol Inzalo Foundation

Quantum degenerate molecular gases are of interest for the unique level of control they offer over chemical interactions and processes. To reach the quantum degenerate regime, these molecular gases must be cooled to ultracold temperatures, typically on the order of 100 nanoKelvins. Unlike atoms, with a few-level system that facilitates cooling, molecules represent a many-level system, which makes these temperatures experimentally difficult to achieve. As a result, experiments have turned to photoassociation and Feshbach resonance as shortcuts to form ultracold molecules from already ultracold atoms. Photoassociation and Feshbach resonance have been utilized to successfully create stable quantum degenerate molecules, but not on a routine basis, and only for a small range of molecular species. The primary focus of this thesis will be to study photoassociation and Feshbach resonance, and investigate possible routes to more efficient long-lived quantum degenerate molecule formation. We will also investigate realistic limiting conditions to open the possibility to more routine molecules, and to molecular species that are currently inaccessible. Overall, we find combined photoassociation and Feshbach resonance are viable schemes for efficiently creating quantum degenerate molecules, under realistic restrictions such as low laser intensity, narrow Feshbach resonance, and strong elastic collisions. As the techniques to create quantum degenerate molecules become more robust and experimentally available, the creation of colder, larger, and more long-lived samples will facilitate study of these molecules, and spur development into new applications. / Physics

It is common to use the electron density to partition a molecular system into atomic regions. The necessity for such a partitioning scheme is rooted in the unquestionable role of atoms in chemistry. Nevertheless, atomic properties are not well- defined concepts within the domain of quantum mechanics, as they are not observable. This has resulted in a proliferation of different approaches to retrieve the concept of atoms in molecules (AIM) within the domain of quantum mechanics and in silico experiments based on various flavors of model theories. One of the most popular families of models is the Hirshfeld, or stockholder, partitioning methods. Hirshfeld methods do not produce sharp atomic boundaries, but instead distribute the molecular electron density at each point between all the nuclear centers constituting the molecule. The various flavors of the Hirshfeld scheme differ mainly in how the atomic shares are computed from a reference promolecular density and how the reference promolecular density is defined. We first establish the pervasiveness of the Hirshfeld portioning by extending its information-theoretic framework. This characterizes the family of f-divergence measures as necessary and sufficient for deriving Hirshfeld scheme. Then, we developed a variational version of Hirshfeld partitioning method, called Additive Variational Hirshfeld (AVH). The key idea is finding the promolecular density, expanded as a linear combination of charged and neutral spherically-averaged isolated atomic densities in their ground and/or excited states, that resembles the molecular density as much as possible. Using Kullback-Liebler divergence measure, this automatically guarantees that each atom and proatom have the same number of electrons, and that the partitioning is size consistent. The robustness of this method is confirmed by testing it on various datasets. Considering the mathematical properties and our numerical results, we believe that AVH has the potential to supplant other Hirshfeld partitioning schemes in future. / Thesis / Doctor of Philosophy (PhD)

Mechanisms for charge transport in organic electronics allows them to perform with disordered internal morphology, something which is not possible for traditional crystalline semiconductors. Improvements to performance can occur when the materials change their relative positions to each other, resulting as a different spatial dispersion with lower electrical loss over the device area. A numerical method has been developed using interaction models for molecules from colloidal self-assembly. Colloids are rigid particles with a volume which is embodied by their shape and their collective behaviour depends on its density. The self-assembly mechanism used is condensation, which increases the density by removing the spaces between molecules while they lose thermal energy due to the increasing steric interactions with neighbours. The molecular chemical structure determines the spatial probability of electron orbitals that (for a given energy) outlines their geometric shape. Because these shapes are localized onto the molecule, their intermolecular positions determine how close these orbitals can be to each other which is important for electron charge transport. During operation, the organic active layer may have thermal energy to cause molecular reorganization before cooling, which increases the probability to find disordered states within the device. A comprehensive suite of tools has been developed which can classify disorder in the physical characteristics of morphology; such as density, internal spacing, and angular orientation symmetry. These tools where used to optimize the experimental preparations for depositing nanoparticle dispersions on surfaces within organic electronic devices. These have also been used to quantify the statistical variations in structure between configurations produced from our Monte Carlo method and a similar molecular dynamics approach. Simulated self-assembly within highly confined areas showed repeatedly sampled microstates, suggesting that at thermodynamic equilibrium confined particles have quantized density states. We conclude with morphologies resulting from non-circular shapes and systems of donor-acceptor type molecules. / Thesis / Doctor of Philosophy (PhD)

Background: Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infection and hospitalization in children worldwide. With no vaccine or antivirals available for the routine prevention or treatment of RSV, an effective RSV antiviral is required. Previous studies have shown that the RSV nucleocapsid complex (NC), phosphoprotein (P), and large polymerase (L) are essential for the replication and survival of RSV since they form the core of the RNA-dependent RNA polymerase (RdRp) complex. Thus, these proteins are viable targets for novel RSV antivirals. Objective: The Mahony laboratory has previously shown that 20 µM of a peptide mimetic composed of the 21 terminal amino acids of the RSV phosphoprotein (RSVP220-241) fused to an HIV-1 Tat cell penetrating peptide (CPP), a hexa-histidine (His) tag, and the Escherichia coli (E. coli) maltose binding protein carrier (MBP) molecule was sufficient to attenuate RSV A and B replication in vitro by approximately 90 and 80%, respectively. We evaluated the fusion of this His-MBP-Tat-RSVP220-241 mimetic to a more suitable carrier molecule, an albumin-binding domain (ABD), for future use in vivo. In addition, we designed a novel antiviral mimetic composed of the 30 terminal amino acids of the RSV A P protein (RSVP212-241), which are involved in binding both L polymerase and NC complexes, fused to a CPP consisting of Tat or nine arginine residues (Arg9), a His-tag, and the MBP carrier. We evaluated the activity of His-MBP-Tat-RSVP212-241, Tat-His-MBP-Tat-RSVP212-241, and His-Arg9-MBP-RSVP212-241 mimetics in vitro and hypothesized that a mimetic designed to target both L and NC interactions would be a more effective RSV antiviral than the original His-MBP-Tat-RSVP220-241 mimetic. Methods and Results: The Gateway® Cloning System was used to create expression vectors containing His-, GST-, or His-MBP-ABD-Tat-RSVP220-241 and His-MBP-Tat-RSVP212-241, whereas inverse PCR and both the In-Fusion® and Gateway® Cloning systems were used to generate expression vectors containing Tat-His-MBP-Tat-RSVP212-241 and His-Arg9-MBP-RSVP212-241. The fusion proteins were expressed, purified by affinity chromatography, and evaluated in vitro. No soluble protein was obtained for the ABD constructs. His-MBP-Tat-RSVP212-241 was toxic and not internalized by LLC-MK2 cells, whereas only 0.26 mg of Tat-His-MBP-Tat-RSVP212-241 was purified. We were able to show that His-Arg9-MBP-RSVP212-241 was non-toxic, internalized, and interacted with the RSV nucleoprotein (N) in a GST pull-down experiment. Furthermore, His-Arg9-MBP-RSVP212-241 attenuated RSV A replication and progeny production by 94.8 and 93.33% at 200 µM, respectively. We demonstrated 50.7 and 49% inhibition of RSV A replication and progeny production at 20 µM, respectively. We showed that inhibition of viral replication by 25 µM His-Arg9-MBP-RSVP212-241 was not significantly different from inhibition by 20 µM His-MBP-Tat-RSVP220-241. Thus, in this thesis we were unable to show that His-Arg9-MBP-RSVP212-241 was a more effective RSV antiviral. Conclusion: The ABD was not a suitable carrier molecule for use with our fusion protein mimetics. However, RSV P protein mimetics that target interactions with the NC complexes and L polymerase are a novel and viable antiviral strategy. We showed that a His-Arg9-MBP-RSVP212-241 mimetic was non-toxic, internalized, and interacted with the RSV N protein in vitro. Furthermore, we showed that at 200 µM this novel mimetic could attenuate RSV A replication and progeny production in vitro by 94.8 and 93.3%, respectively. Further studies are required to characterize the construct, increase its bioactivity, and identify a suitable human carrier molecule for future evaluation in vivo. / Thesis / Master of Science (MSc) / Worldwide, respiratory syncytial virus is a leading cause of lower respiratory infection and hospitalization in children. Nearly all children are infected with the virus by the young age of two. However, respiratory syncytial virus also causes a significant amount of illness and death in the elderly and in immunocompromised individuals. Furthermore, repeated infections by the virus are common throughout life in all populations. With the lack of a vaccine or treatment for this viral infection, an effective antiviral against RSV is required. In this thesis, we developed and evaluated a novel RSV antiviral therapeutic peptide that targets proteins of the viral replication machinery. Since the replication machinery is required for respiratory syncytial virus survival, we hypothesized that infection could be attenuated by preventing formation of the replication machinery. Furthermore, since small protein therapeutics are often cleared quickly from the human body, we investigated human carrier molecules that could be attached to the antiviral protein for stabilization within the body.

Fouling properties of materials such as polyethylene glycol (PEG) have been extensively studied over the past decades. Traditionally, the factors believed to result in protein adsorption resistance have included i) steric exclusion arising from the compression of longer chains and ii) grafting density contribution which may provide shielding from the underlying material. Recent studies have suggested that PEG interaction with water may also play a role in its ability to resist protein adsorption suggesting that steric exclusion may not be the only mechanism occurring during PEG/protein interactions. Star-shaped PEG polymers have been utilized in protein adsorption studies due to their high PEG segment concentration, which allows to increase the PEG chain grafting density compared to that achieved with linear PEG chains. Most studies that have investigated the interactions of tethered linear and star-shaped PEG layers with proteins have considered linear PEG molecules with molecular weights several orders of magnitude smaller than those considered for star-shaped PEG molecules (i.e. 10 000 g/mol vs. 200 000 g/mol, respectively). Additionally, the star-shaped PEG molecules which have been considered in the literature had up to ~70 arms and were therefore modeled by hard-sphere like structures and low chain densities near the surface due to steric hindrance. This resulted in some difficulties to achieve grafted PEG chain overlap for star molecules. Here, triethoxysilane end-functionalized linear PEG molecules have been synthesized and utilized to form star-shaped PEG derivatives based on ethoxy hydrolysis and condensation reactions. This resulted in PEG stars with up to ~4 arms, which were found to result in grafted star-shaped PEG chains with significant chain overlap. Linear PEG derivatives were synthesized so that their molecular weight would match the overall molecular weight of the star-shaped PEG molecules. These 2 PEG molecular architectures were covalently self-assembled to hydroxylated silicon wafers and the thickness, grafting density, and conformation of these films were studied. The adsorption of human albumin (serum protein) on linear and star-shaped PEG films was compared to that obtained on control samples, i.e. uncoated silicon wafers. Both film architectures were found to significantly lower albumin adsorption. / Ph. D.