Browsing by Subject "chemistry"

Now showing 1 - 13 of 13
  • Thumbnail Image
    Item
    Open Access
    Asymmetric Total Synthesis of the Pentacyclic Indole Alkaloid (+)-Tacamonine
    (2019) Ferreira, Jasmin; Hunter, Roger
    (+)-Tacamonine, a natural product isolated from the Central African plant Tabernaemontana eglandulosa, belongs to the relatively new tacaman class of pentacyclic monoterpenoid indole alkaloids. Its close structural similarity to the potent cerebral vasodilator (-)-vincamone has promoted several efforts towards its synthesis, culminating in the appearance of two asymmetric and seven racemic syntheses in the literature. This dissertation details the successful execution of our strategy for the concise, highly-efficient, asymmetric total synthesis of (+)-tacamonine. Chapter 1 serves as an introduction to the tacaman class, including the proposed biosynthesis for members of this class, followed by a review of the reported synthetic approaches to tacamonine. Chapter 2 details the evolution of our approach based on the use of key radical cyclization methodology to ultimately accomplish a total synthesis of the target. An investigation of the diastereoselectivity displayed in the radical cyclization step is also described through computational methods. Our route followed a novel ABC to ABCD to ABCDE ring-construction strategy, which first involved the synthesis of 3,4-dihydro--carboline as well as a chiral acid ester fragment that was acquired through Evans’ auxiliary-controlled alkylation chemistry. The latter set the absolute configuration at C-20 bearing the ethyl group in the D-ring, and thereafter, the two fragments were coupled together before being advanced to the radical cyclization precursor. Radical cyclization then led to the formation of the desired cis D/Ering junction in a diastereomeric ratio of 10:1, the major diastereomer displaying the required C-3/C-14 to C-20 anti-diastereoselectivity. Subsequent global reduction and oxidation/E-ring formation processes afforded the target in 8 steps over 10 operations in 25% overall yield and in 96% enantiomeric excess. X-Ray crystallographic structure determination provided conclusive evidence for the formation of the target.
  • Thumbnail Image
    Item
    Open Access
    Development of dermally absorbed copper(ii) complexes as potential anti-inflammatory drugs
    (2021) Vicatos, Giselle Marianthi; Jackson, Graham E; Bourne, Susan A
    Rheumatoid arthritis (RA) is a debilitating disease affecting 5% of the world's population and there is no cure. Copper(II) complexes have been reported to have anti-inflammatory activity and alleviate the symptoms associated with the disease. The present study focuses on the design of new drugs that could be used to change the bioavailability of copper(II) and hence alleviate the inflammation. The tripeptides, glycyl-L-leucyl-L-histidine (GLH), sarcosyl-L-leucyl-Lhistidine (Sar-LH), glycyl-L-phenylalanyl-L-histidine (GFH) and sarcosyl-L-phenylalanyl-Lhistidine (Sar-FH) were designed to resemble the natural in vivo copper(II) transporter, human serum albumin, so that they could be selective for copper(II). The preferred route of administration is dermal absorption and so sarcosine was added to improve the lipophilicity of the drug. This administration method was chosen since it is both nonharmful and convenient for patients. The stability of the complexes was measured using glass electrode potentiometry and their solution structure studied using UV-Vis spectrophotometry, CW-EPR spectroscopy, 1H NMR, ESI-MS and molecular modelling calculations. The presence of sarcosine did not significantly affect the stability of the complexes. Several species were found to exist in solution depending on the pH, but at pH 7, the CuLH-2 species predominated for all four tripeptides. In this species, the ligand was found to coordinate to copper(II) via the terminal amine-N, the two amide-Ns and imidazole-N, in a square planar geometry. Using a computer model of blood plasma, all four ligands were found to mobilise copper(II), without disrupting the homeostasis of nickel(II), zinc(II) or calcium(II) in the order of GFH > Sar-FH > GLH > Sar-LH. GFH increased the low molecular mass copper(II) species by 40.7 times at 0.1 mM. The lipophilicity of the complexes was estimated by measuring their octanol/water partition coefficients. All the complexes were found to be hydrophilic with log Poct/aq ranging from -3 to -2. Dermal absorption was estimated using an artificial membrane and a Franz cell. Only a moderate increase in membrane permeability of copper(II) was found. The stability of the copper(II) complexes, their ability to mobilise copper(II) from endogenous sources and their improved dermal absorption, justifies further testing of this class of ligand as potential, dermally absorbable, anti-inflammatory drugs.
  • Thumbnail Image
    Item
    Open Access
    Encapsulation of iron(III) protoporphyrin IX and tetraphenylporphyrin in metal-organic frameworks for application as heterogeneous oxidation catalysts
    (2018) Dare, Nicola A; Egan, Timothy John; Bourne, Susan
    Two MOFs, [H2N(CH3)2][Zn3(TATB2(HCOO)]·HN(CH3)2·DMF·6H2O (1) and ZnHKUST-1 (2) (TATB = 4,4′,4″-s-triazine-2,4,6-triyl-tribenzoate) were investigated as potential hosts to encapsulate Fe(III) protoporphyrin IX (ferrihaem = Fe(III)PPIX) and Fe(III) tetraphenylporphyrin (Fe(III)TPP). Methyl orange (MO) adsorption was used as an initial model for substrate uptake in MOFs 1 and 2. MOF 1 showed good adsorption of MO (10.3 ± 0.8 mg.g-1 ) which could undergo in situ protonation upon exposure to aqueous HCl vapour. By contrast MO uptake by 2 was much lower (2 ± 1 mg.g-1 ) and PXRD indicated structural instability on exposure to water was the likely cause. Two methods for Fe(III)PPIX incorporation into 1 were investigated: soaking and encapsulation. Encapsulation was verified by SEM-EDS and showed comparable concentrations of Fe(III)PPIX on exposed interior surfaces and on the original surface of fractured crystals. SEM EDS results were consistent with ICP-OES data on bulk material (1.2 ± 0.1 mass % Fe). PXRD data showed that the framework in 1 was unchanged after encapsulation of Fe(III)PPIX. MO adsorption (6 ± 1 mg.g1 ) by Fe(III)PPIX-1 confirmed there is space for substrate diffusion into the framework, while the UV-visible spectrum of solubilized crystals confirmed that Fe(III)PPIX retained its integrity. A solid-state UV-visible spectrum of Fe(III)PPIX-1 indicated that Fe(III)PPIX was not in a µ-oxo dimeric form. Although single-crystal XRD data did not allow for full refinement of the encapsulated Fe(III)PPIX molecule owing to disorder of the metalloporphyrin, the Fe atom and pyrrole N atoms were located, enabling rigid-body modelling of the porphine core. For comparison, Fe(III)PPIX was further encapsulated in 2, forming Fe(III)PPIX-2. Reaction ABSTRACT of 2,2'-azino-bis(3-ethylbenzothiazoline)-6-sulphonic acid (ABTS) with H2O2, catalysed by Fe(III)PPIX-1 and -2 showed that Fe(III)PPIX-1 is significantly more efficient than Fe(III)PPIX-2 and is superior to solid Fe(III)PPIX-Cl due to the faster initial rate of reaction as well as the greater conversion of ABTS to ABTS●+ . Both frameworks 1 and 2 were also investigated as potential hosts to encapsulate Fe(III) tetraphenylporphyrin (Fe(III)TPP). Attempts to encapsulate Fe(III)TPP into 1 were unsuccessful, but Fe(III)TPP was successfully encapsulated into 2, forming Fe(III)TPP-2. The framework was characterised by PXRD and SEM-EDS confirmed uniform distribution of Fe(III)TPP through the framework. The loading of Fe(III)TPP determined using ICP-OES (0.604 ± 0.008 Fe mass %) agreed well with SEM-EDS data. Single crystals of Fe(III)TPP-2 were obtained and structure determination showed that the Fe(III) porphyrin was positionally disordered over three positions. The instability of Fe(III)TPP-2 in the presence of H2O resulted in it being an inappropriate choice as an oxidation catalyst. The kinetics of ABTS oxidation by H2O2 catalysed by Fe(III)PPIX-1 were further investigated. The peroxidatic activity of this heterogeneous system conforms to a rate law identical to that observed in solution with no discernible influence of particle size, suggesting that the MOF system closely mimics the solution state. The proposed rate law indicates a reaction mechanism with two possible pathways, as suggested for the same reaction in solution. The major pathway describes the coordination of H2O2 to the Fe(III) centre and subsequent formation of a high valent intermediate, while the minor pathway describes the same process preceded by ABTS coordination to the Fe(III) centre forming a six-coordinate complex. The further application of Fe(III)PPIX-1 as an oxidation catalyst was probed by investigating the catalytic oxidation of hydroquinone, thymol, benzyl alcohol and phenyl ethanol by tert-butyl-hydroperoxide ( tBuOOH). Reactions were successful and showed t1/2 values that increase with increasing substrate molecular volume.
  • Thumbnail Image
    Item
    Open Access
    Measuring the impact of academic development courses in first-and second-year chemistry
    (South African Chemical Institute, 2013) Smith, Leonard C
    This paper uses multivariate analysis to estimate the impact of educational interventions in the first-year academic development chemistry courses on students' final course marks. The cohorts for seven years are pooled, which generates a more robust set of results than was previously the case. To counter the sample-selection problem that arises as academic development students are placed onto the academic development programme, a selection of control variables is included in the estimations. The results suggest that the educational interventions in the first year had a positive impact on academic development students' performance, relative to mainstream students, in both the first- and second-year courses. The implications of the results for education policy and research are considered.
  • Thumbnail Image
    Item
    Open Access
    Monometallic and multimetallic complexes as precatalysts in the hydroformylation of olefins
    (2020) Siangwata, Shepherd; Smith, Gregory S; Goosen, Neill J
    A series of new aryl ether salicylaldimine-based monomeric, dimeric, trimeric and hexameric triazolyl ligands have been synthesised. The N,O-chelating ligands were synthesised via Schiff base condensation reactions of salicylaldehyde with the bromopropylamine hydrobromide salt, followed by the azidation of the resultant N-3-bromopropylsalicylaldimine. Click chemistry reactions of the azido propyl salicylaldimine with the appropriate phenolic-alkyne afforded the mono-, di-, tri- and hexameric aryl ether salicylaldimine-based triazolyl ligands. The ligands were characterised using various analytical and spectroscopic techniques. Complexation of the monomeric and trimeric ligands with the dimeric rhodium precursor [RhCl(COD)]2 yielded new aryl ether N,O-chelate mononuclear and trinuclear Rh(I) complexes. The complexes were characterised using nuclear magnetic resonance spectroscopy, infrared spectroscopy, mass spectrometry and melting point determinations. The mononuclear and trinuclear complexes were successfully evaluated as catalyst precursors in the hydroformylation of higher olefins. The reaction conditions were optimised using the mononuclear precatalyst at 85 ℃, 40 bar syngas pressure for 4 h with 2.87 x 10-3 mmol Rh loading and a substrate (1-octene) to catalyst ratio of 2500 : 1. These conditions gave good aldehyde chemoselectivity (90%), excellent conversion of the substrate (99%) and good catalytic activity (554 h-1 ). Comparable catalytic performance of both precatalysts was obtained when milder reaction conditions (85 ℃, 20 bar for 4 h) were adopted in the evaluation of the mononuclear complex against the low generation dendritic trinuclear complex. The mercury poisoning experiments revealed a dual catalytically influenced system, emanating from a combination of homogeneous and heterogeneous catalytic species. The mononuclear catalyst precursor was also evaluated successfully in the hydroformylation of internal olefins 7- tetradecene and trans-4-octene. The catalyst precursor gave good conversions of both internal olefins (> 80%) under the optimum reaction conditions (85 ℃, 40 bar for 4 h). Catalyst recyclability studies in the hydroformylation of 1-octene conducted using the Organic Solvent Nanofiltration (OSN) strategy demonstrated five successful recycles with consistently good catalytic performance from both catalyst precursors. Inductively coupled plasma optical emission spectrometry (ICP-OES) experiments revealed a near perfect (99%) membrane retention of the rhodium metal. Kinetic studies using the mononuclear precatalyst were investigated by evaluating the effect of temperature, syngas total pressure and catalyst loading on the rate of hydroformylation. The activation energy for the hydroformylation of 1-octene was calculated to be 62 kJ mol-1 and the experimental rate constants were found to be in good agreement with the predicted rate data obtained using a modified fundamental mechanismbased rate model. The synthesis and characterisation of new water-soluble, sulfonated aryl ether salicylaldiminebased mono- and trimeric ligands has also been described. The ligands were prepared following a series of amine and Boc-protection and deprotection procedures, Schiff base condensation reactions and Williamson ether synthesis. The water-soluble N,O-chelating aryl ether ligands were characterised using various spectroscopic and analytical techniques. Subsequently, complexation reactions of the ligands with the dimeric [RhCl(COD)]2 gave the corresponding new water-soluble mononuclear and trinuclear Rh(I) complexes. The complexes were characterised using nuclear magnetic resonance spectroscopy, infrared spectroscopy, mass spectrometry and melting point determinations. The complexes show appreciably good solubility in water, 15.7 mg/mL (mononuclear complex) and 8.6 mg/mL (trinuclear complex). The new water-soluble mono- and trinuclear complexes were successfully evaluated as precursors in the aqueous biphasic hydroformylation of higher olefins. Optimisation experiments using the mononuclear precatalyst gave the best results at 85 ℃, 50 bar syngas pressure for 4 h with 2.87 x 10-3 mmol Rh loading and a substrate (1-octene) to catalyst ratio of 2500 : 1. Both catalyst precursors gave near quantitative catalytic conversion of 1-octene, good activities (> 550 h -1 ) and attractive aldehyde chemoselectivity (> 85%). A substrate and product-distribution time study showed a positive dendritic effect in relation to the trinuclear complex over the mononuclear complex. The mercury poisoning experiments were suggestive of a system that is catalysed by a dual effect of homogeneous and heterogeneous catalytic species. Recyclability experiments were successfully conducted over 5 cycles, with a gradual decline in catalytic performance for both complexes. The dendrimer stabilised trinuclear precatalyst showed improved recyclability in “neat”, monophasic hydroformylation experiments, while the mononuclear precatalyst showed a reduced overall performance. The bias towards the linear aldehyde for the dendritic trinuclear complex was tunable by addition of excess bulkier trimeric water-soluble ligand into the catalytic system. Inductively coupled plasma optical emission spectrometry experiments showed moderate losses of the metal from the aqueous phase to the organic layer. Both catalyst precursors also showed good catalytic activity (> 450 h-1 ) and a total bias to aldehyde chemoselectivity (no hydrogenation products) in the aqueous biphasic hydroformylation of styrene.
  • Thumbnail Image
    Item
    Open Access
    Repositioning of astemizole for malaria
    (2021) Mambwe, Dickson; Chibale, Kelly
    Malaria remains one of the most important parasitic infectious diseases as far as human suffering is concerned. With almost half of the world's population at risk, its burden is felt worldwide as seen by the high number of deaths recorded each year (405,000 in 2018: WHO World Malaria Report 2019). Unfortunately, over 90% of this mortality rate is recorded in Africa alone, with the highest risk being in children under the age of five (5) and pregnant women. Partly, this is due to the unfortunate spread of resistance to most drugs that were once effective and safe, including Artemisinins which form the basis of the current first-line regimen in the treatment of malaria. For this reason, it is crucial to invest research efforts using various approaches in the drug discovery arsenal to develop novel, and structurally diverse antimalarials with different modes of action. These new antimalarials should not only be able to circumvent resistance but need to be efficacious at different life cycle stages of the parasite (multi-stage activity). This Ph.D. project pursued a drug repositioning approach on Astemizole (AST, Figure 1), a second-generation antihistamine drug which was previously identified as an antimalarial agent by Chong et al., at the Johns Hopkins University School of Medicine through via a high-throughput screening (HTS) of diverse marketed drugs. AST was active against chloroquine-sensitive (CQ-S) and multi-drug resistant (MDR) laboratory strains of the human malaria parasite Plasmodium falciparum (P. falciparum) and demonstrated in vivo efficacy in two mouse infection models of malaria namely, P. Vinckei and P. Yoelii. However, in addition to its low solubility, AST possesses a serious and fatal cardiotoxicity risk, evidenced by its ability to potently inhibit the human ether-á-go-go-related gene (hERG) encoded potassium (K+) channels. This liability led to the withdrawal of AST in most countries during the late 1970's and it is still being discontinued for use in some countries to date.
  • Thumbnail Image
    Item
    Open Access
    Selectivity in host-guest compounds
    (2022) Sykes, Nicole M; Nassimbeni, Luigi R; Bourne Susan A
    It isn't easy to separate structurally similar guests by conventional methods such as distillation if the mixture components have similar functional groups and boiling points. This thesis aimed to investigate the relationship between the internal structures of host-guest compounds and the selectivity shown by the host molecule when presented with a guest mixture. Four host compounds were used to prepare 29 new inclusion compounds. Two of these hosts were similar bulky diols and were synthesised by Weber (H1 and H2). The other two, a Nibased Werner-type host (H3) and a brominated host (H4), were synthesised by known methods. In addition, two new structures of the host, H1, alone are reported. Inclusion compounds were prepared by recrystallising the host from liquid guests or exposing the powdered host to guest vapours. The internal structure of the resulting compounds was determined by single crystal X-ray diffraction (XRD), and the secondary interactions between host and guest were carefully studied. The thermal stability of compounds was measured using differential scanning calorimetry, and thermal gravimetry – the latter of which also confirmed the ratio of host to guest within compounds. The preference of a host for one guest over another was determined by exposing the host to mixtures of guests, waiting for crystals to form, and then subjecting these crystals to 1H nuclear magnetic resonance (NMR) spectroscopy or gas chromatography (if guest molecules were indistinguishable by NMR). In some cases, the kinetics of host-guest compound formation and guest exchange was monitored by powder XRD, using an in-house custom-built sample holder. These techniques allowed for the measurement of the relative proportions of guests in the crystals, which was then compared to the ratio of guests from which the host was initially recrystallised. In some cases, it was found that the thermal stability of host-guest compounds correlates with the guest preference of the host. I.e., the guest that formed the most thermally stable host-guest compound is the guest the host prefers. However, it was not always possible to assign structural reasons why this should be the case. In one example, the selectivity of a host was dependent on the temperature of recrystallisation. In another system, the inclusion compound crystallised from a guest mixture had a different structure than when crystallised from either individual guest. In addition, this host's selectivity decreased with time and increasing guest concentration, with concomitant structural changes. While much progress has been made in predicting the structures of single-component crystals, it is still not possible to predict the structures of crystals with multiple components. With the view to predicting the required conditions to grow materials with desired properties, such as being highly selective, more studies on polymorphic inclusion compounds formed under different crystallisation methods are needed.
  • Thumbnail Image
    Item
    Open Access
    Structure activity and structure property relationships of antimalarial imidazopyridazines
    (2019) Centani, Luyanda; Chibale, Kelly
    Malaria is one of the most pressing human health issues. Despite being an ancient disease, it is estimated to have an annual death rate of 445 000 with out of 216 million malaria related cases in 2016. Malaria is most widespread in developing regions of the world. Forty percent of the world’s population is exposed to varying degrees of malaria. Malaria is caused by different species of the Plasmodium genus and the disease is vector-borne. The disease may be cured if diagnosed early. Most drugs that were once effective in the treatment of malaria have become ineffective due to the emergence of resistance, which has become the main driving force behind efforts to discover and develop new drugs able to circumvent the resistance. Imidazopyridazines have been shown to have potent antiplasmodium activity. The lead compound MMV652103 has been shown to display potent activity against the multidrug resistant K1 strain and the drug sensitive NF54 strain of the human malaria parasite Plasmodium falciparum. However, the majority of the antimalarial imidazopyridazine compounds evaluated to date have solubility and off-target human ether-a-go-go-related gene (hERG) potassium ion channel liabilities. Towards improving solubility and de-risking the hERG liability, a series of analogues was designed and synthesised. Structure-Activity Relationship (SAR) and Structure-Property Relationship (SPR) studies aimed at retaining the good antiplasmodium activity while improving solubility and reducing hERG channel inhibition, were conducted. Previous studies conducted on this series of imidazopyridazines have shown that incorporation of hydrogen bond donors or acceptors resulted in improving solubility and hERG channel inhibition. While the lead compound MMV652103 at pH 6.5 has a sub-optimal solubility of 5 µM, all target compounds showed an improvement in solubility. Five analogues 59, 78, 84, 85, and 86 exhibiting impressive in vitro asexual blood stage antiplasmodium potency (IC50< 100 nM) and aqueous solubility (> 200 µM) were identified from the study. The identified compounds also displayed good activity against the sexual late-stage gametocytes, the transmissible forms of the parasite.
  • Thumbnail Image
    Item
    Open Access
    Syntheses of luciferins and their bioluminescent evaluation
    (2018) Rylands, Marwaan; Jardine, Mogamat
    Luciferins are a class of light emitting small molecule substrates. These molecules are oxidised to produce visible light in a reaction catalysed by the luciferase enzymes. The combination of this luminescent reaction coupled with CCD cameras, has produced revolutionary technologies that enable measurements of mammalian gene expression in cells, as well as protein-protein interactions, biochemical labelling, and small molecule flux, to name a few. Of all the luciferin molecules, D-luciferin is the most widely researched. D-Luciferin is the light emitting molecule isolated from the American firefly Photinus pyralis (Ppy). Synthetic D-luciferin has become increasingly valuable since its incorporation into a growing number of commercially available assays kits, where the molecule is used as a sensitive reporter both in vitro and in vivo. This thesis focuses on improved methods of preparing synthetic D-luciferin and related C6-analogues, as well exploring the bioluminescent properties of a novel C6-thio analogue of D-luciferin. The novel analogue was targeted to provide an alternative or complementary substrate for bioluminescence imaging, that would allow for bioluminescence to be applied in systems where traditional D-luciferin application was limited. In the first part of the thesis, D-luciferin and a C6-amino analogue of D-luciferin, D-aminoluciferin, were prepared using both reported and newly developed procedures. The new methodology afforded the luciferins in improved overall yields and, it was further demonstrated that the new sequence, unlike its palladium-based counterpart, is more scalable, has better functional group tolerability and is relatively greener. The second part of the thesis focuses on the preparation and bioluminescent evaluation of a novel C6- thio analogue of D-luciferin. The new luminogenic substrate, D-thioluciferin, displayed a lower Km and a more red-shifted maximum emission, but with a much lower luminescent output relative to D-luciferin. The thiol handle of D-luciferin and its bioluminescence properties were then explored for potential glutathione reductase (GSR) monitoring, where a D-thioluciferin disulfide was successfully and directly applied to GSR activity sensing. The improved methods of preparation and the novel thioanalogue described in this thesis both contribute to bettering and broadening luciferin-based applications by providing more efficient access to known luciferins, and by increasing the number of luciferin substrate options for bioluminescent research and applications.
  • Thumbnail Image
    Item
    Open Access
    Synthesis and evaluation of D-cycloserine analogues against mycobacterium tuberculosis
    (2020) Renga, Shoneeze Simone; Chibale, Kelly; Singh, Vinayak
    Tuberculosis (TB) continues to be the leading cause of death from a single infectious agent worldwide. The rapid emergence of multidrug-resistant and extremely drug-resistant underpin the urgent need for novel, safe and efficacious drugs. D-Cycloserine (DCS) is an oral bacteriostatic anti-tubercular drug used for the treatment of drug-resistant TB. Despite attractive properties, DCS displays significant toxicity at effective dosages. However, a synthetic analogue of DCS, terizidone, has shown an improved safety profile. This study focused on the synthesis of two new classes of DCS analogues: isoxazolidin-3-oneimines (ISIs) and 3-isoxazolidin-4-yl amides (ISAs). These analogues were designed to act as potential prodrugs. In an effort to explore structure-activity-relationships, a total of 17 compounds were synthesized, fully characterized, and evaluated in vitro for their antimycobacterial activity against the drug-susceptible Mtb H37Rv strain cultured in 7H9/ADC media. Of these, two compounds displayed noteworthy antimycobacterial activity (MIC99 ≤ 10 μM). In addition to this, all 17 compounds manifested low cytotoxicity (IC50 > 25 μM) when tested in vitro against the chinese hamster ovarian cells and the human hepatocytes cells. Furthermore, a selected potent compound displayed high microsomal metabolic stability in rat, mouse and human liver microsomes. The kinetic solubility of the target compounds was determined using a HPLC-based method. The solubility data obtained was then correlated with melting point, tPSA and cLogP in order to establish structuresolubility relationships across the two compounds series. Solubility was strongly correlated to melting point in the IZAs series (R2 = 0.9318) and moderately correlated to tPSA for IZIs (R2 = 0.164, whereas there was no correlation between solubility and cLogP (lipophilicity) in either class of compounds (R2 = 0.085 for IZIs and R2= 0.0004 for ISA).
  • Thumbnail Image
    Item
    Open Access
    Synthesis, characterisation and pharmacological evaluation of silicon-containing aminoquinoline organometallic complexes as antiplasmodial, antitumor and antimycobacterial agents
    (2013) Li, Yiqun Tony; Smith, Gregor; Chibale, Kelly
    The medical success of platinum-based compounds such as cisplatin and its analogues laid the foundation for the synthesis and application of new transition metal complexes in the field of medicine. With the discovery of additional transition metal-based compounds such as ferroquine, KP1019 and NAMI-A, as therapeutic agents for the treatment of different diseases, the field of novel pharmacological transition metal agents continues to evolve. The constant increase in drug resistance and various undesirable side effects of current available therapies has led to the search for new strategies. Identifying novel drug candidates through utilising different metals of biological relevance is one such approach, and the main purpose of this study. New mono- and heteronuclear silicon-containing ruthenium and rhodium metal complexes based on two ligand classes, have been synthesised and characterised utilising a range of analytical and spectroscopic techniques, confirming the structural integrity. The first class of compounds was constructed from a chloroquine derivative, and was synthesised via a general Schiff-base condensation reaction. Two silicon-containing aminoquinoline ligands 2.1 and 2.2 were derived from chloroquine, modified in the lateral side chain with organosilicon moieties. Compounds 2.1 and 2.2 were further reacted with dinuclear halfsandwich transition metal precursors [Ru(Ar)(µ-Cl)Cl]i (Ar = 116 -p-iPrC6H4Me; 116 -C6H6; 116 -C6HsOCH2CH2OH), [Rh(COD)(µ-Cl)h, and [RhCp *{µ-Cl)Clh, to yield a series of neutral mononuclear Ru(II), Rh(I/111) silicon-aminoquinoline metal complexes 2.8-2.17. Ligands 2.1 and 2.2, act as monodentate donors that selectively coordinate to the transition metals via the quinoline nitrogen of the aminoquinoline scaffold. Furthermore, the molecular structures of compounds 2.2 and 2.16 were elucidated by single-crystal X-ray diffraction analysis. A second class of compounds based on the ferroquine scaffold was synthesised from ferroquine, again incorporating a organosilicon motif in the lateral side chain. Compound 3.6 was further reacted with the afore-mentioned Ru and Rh dinuclear half-sandwich transition metal precursors to yield a series of neutral heteronuclear Ru(II) and Rh(I/111) siliconcontaining ferrocenyl aminoquinoline metal complexes 3.7-3.11 isolated in moderate yields. Compound 3.6 coordinates to the metal in a similar manner to ligands 2.1 and 2.2 (via the quinoline nitrogen), and all the complexes 3.7-3.11 were fully characterised confirming the structural integrity. Furthermore, the molecular structure of compound 3.6 was elucidated by iii single-crystal X-ray diffraction analysis, showing the ferrocene and organosilicon motifs incorporated into the lateral side chain of the quinoline scaffold. The in vitro pharmacological activities of the synthesised compounds were established against chloroquine-sensitive (NF54) and chloroquine-resistant (Dd2) strains of the malarial parasite, Plasmodium falciparum, and against the pathogenic bacterium, Mycobacterium tuberculosis H31Rv, as well as an oesophageal (WHCO 1) cancer cell line. All compounds were found to exhibit moderate to high antiplasmodial activities against the NF54 and Dd2 P. falciparum strains, with IC50 values in the nanomolar range for the ferroquine-derivatised series. The heterometallic series shows superior biological activity, suggesting that different metals may interact with multiple biological targets, providing chemical diversity, thus improving the physicochemical properties. The IC50 values of compounds 3.7-3.11 are comparable to ferroquine, and in selective cases, better than the current clinical antiplasmodial agent chloroquine. Furthermore, the more lipophilic ferroquine-derivatised series, displayed better inhibition of 13-haematin through superior accumulation in the food vacuole of the parasite, and therefore better at killing the malaria parasite. All compounds exhibited weak to moderate antitumour activities. The studies also showed that the ruthenium metal complexes generally display better activity in comparison with the rhodium complexes, and the compounds containing a 3-carbon chain spacer generally show better activity in comparison to those containing a I-carbon spacer. The presence of the metal moiety did not significantly enhance the biological activities in comparison with the organic ligands. In general, all compounds exhibited weak to moderate antimycobacterial activities against M tuberculosis H37Rv strain. Overall, the turbidimetric solubility assay data suggests that these newly synthesised silicon-containing chloroquine and ferroquine derivatives are relatively good drug candidates for in vitro pharmacological testing. All compounds showed moderate solubility in the aqueous PBS buffer.
  • Thumbnail Image
    Item
    Open Access
    Synthesis, structure and properties of novel Cu(II)-based metal-organic frameworks
    (2019) Bardini, Marco; Bacchi, Alessia; Bourne, Susan; Zacharias, Savannah
    Porous crystalline materials are known to be useful for a number of applications, including sensing, 1 drug delivery, 2 solid state catalysis3 and controlled absorption and release of liquids, gases and small molecules in solution. 4,5 Within this general definition, a class of materials that has seen its importance grow exponentially in the past two decades has been that of the Metal-Organic Frameworks, or MOFs. These materials have shown a lot of potential, especially in devices aimed at sequestering greenhouse gases (such as CO2 and CH4) from the atmosphere, 6 as well as in fuel tanks for hydrogen-powered cars. 7 The characteristics that allow MOFs to be used for such purposes are their high internal surface area to volume ratio, their relatively high thermal stability and the possibility to fine-tune their structure to optimize a given MOF for a given application. 8 Another feature of some MOFs, especially those built with semiflexible organic linkers9 between metallic nodes, is that they can change their conformation and therefore their pore size and internal surface area, in response to an external stimulus. 2,10 This behavior is especially interesting for systems which can be engineered to absorb and then release small molecules in a controlled manner. 11,12 This last property is one that I set out to exploit in my thesis work, starting from Cu(II) molecular complexes previously synthesized in the University of Cape Town (UCT) laboratories and varying experimental conditions in order to get MOFs of similar systems. Thus, this work will mainly describe the several novel crystal structures I obtained during my research. Each chapter will also discuss the basic spectroscopic and thermal properties of the material explored therein. Of these crystals, two are novel Cu(II)-based coordination polymers, which were named 1-MBUCT and 2-MBUCT, with seldom-seen coordination characteristics and other interesting features, including solvent-filled cavities within their crystal structure, which makes them promising candidates to be fully considered MOFs. After exploring the synthesis and structure of the materials, this work will mainly focus on determining whether the cavities inside 1-MBUCT and 2-MBUCT are accessible to other guests, without disrupting the overall morphology of the material. This was done through solvent exchange experiments, which were inconclusive but nonetheless suggested that these materials did indeed retain their shape, while allowing guest molecules inside their pores, thus being worthy of being described as MOFs. 6 All other structures are byproducts obtained during various attempts to optimize the synthesis of these MOFs, and are often examples of unusual compound classes in their own right. The first of these compounds is a Cu-based [12]crown-6 cyclical compound in which two monomethyl sulfide anions for every copper ion act as bridging ligands within the ring-like structure of the molecule, while the second is a discrete molecular complex formed by two 2,6- pyridinedicarboxylic acid molecules chelating a Cu(II) ion. The main point of interest of the last byproduct, instead, is not its structure, but rather the fact that all the carboxylic acid groups of the 3,5-pyridinedicarboxylic acid molecules included in the complex were subject to an esterification reaction. Such a reaction was unexpected, as the components of this system did not correspond to those found in any reported esterification reaction performed on 3,5-pyridinedicarboxylic acid.
  • Thumbnail Image
    Item
    Open Access
    Synthesis, structure-activity relationship and solubility improvement studies of potential antimalarial and antischistosomal pyrido[1,2-a]benzimidazoles
    (2019) Chisanga, Kelly; Chibale, Kelly
    In 2016, 216 million malaria cases with 445,000 associated deaths were recorded according to the World Health Organization (WHO). Schistosomiasis also remains a public health issue with 207 million cases recorded globally and 280,000 deaths in the same year. Widespread emergence of parasite resistance to once-effective antimalarial options has rendered currently used drugs ineffective. Moreover, the current WHO-recommended first-line antimalarial drugs in clinical use, the artemisinin combination therapies (ACTs) are faced with the challenges of limited availability, unaffordable cost, and undesirable adverse effects. On the other hand, the treatment of schistosomiasis is severely limited to one treatment regimen, praziquantel (PQZ) which, unfortunately, has recently shown low curing rates in some parts of West Africa. Furthermore, this treatment option is far from ideal because its activity is limited to only adult schistosomes while displaying no activity towards young stages of the liver flukes. These challenges collectively provide a justification for stepping up drug discovery and development efforts aimed at identifying novel, safe and efficacious antimalarial and antischistosomal agents. Whereas, the pyrido[1,2-a]benzimidazole (PBI) scaffold is found in many pharmacologically relevant molecules including Rifaximin, an approved gastrointestinal antibacterial drug, medicinal chemistry explorations around the PBI nucleus have recently identified analogues as novel antimalarial and antischistosomal agents. Additionally, while promising antimalarial efficacy has been demonstrated in animal studies, preliminary in vitro studies of the PBI class of compounds have also demonstrated good activity against Schistosoma parasites. Recently, Mayoka reported the impressive dual antiparasitic potency of the lead compound GMP-19 (figure 1) against Plasmodium and Schistosoma parasites in vitro (IC50 = 0.430 μΜ, drug sensitive strain (NF54) and IC50 = 0.210 μΜ, adult S. mansoni, (unpublished data)). However, GMP-19 and other PBI analogues in this series of compounds, have been beset by poor solubility. Towards addressing solubility issues while retaining and improving antiparasitic activity, in this MSc dissertation, the design, synthesis, structure-activity relationship (SAR) and solubility improvement studies of PBI analogues based on the GMP-19 template are reported. In this regard, chemical modification approaches such as disruption of molecular planarity, increasing saturation, incorporating water solubilizing groups such as the polar-ionizable and the neutralpolar functionalities around the PBI nucleus were adopted. Consequently, we obtained SAR 1analogues after substituting the 4-(trifluoromethoxy)phenyl (4-OCF3Ph) moiety of GMP-19 with assorted α-methyl benzylamines. In addition, the phenyl ring on the left-hand side of the core scaffold was substituted with electron withdrawing groups such as the chloro and fluoro atoms (SAR 1.1 - 1.4), (figure 1). Although some analogues demonstrated a significant loss of antiparasitic activity (> 6.00 μM), strong submicromolar antiparasitic activity was observed with most analogues (IC50 = 0.022 -0.940 μM, PfNF54 and 30 - 69% inhibitory effect at 0.370 μM, against young forms of S. mansoni). Moreover, some analogues demonstrated poor solubility as low as < 10 μM while others showed highly improved solubility as good as 80 μM. In SAR 2.1 - 2.2, the 4-OCF3Ph and the trifluoromethyl (CF3) on the right-hand side (RHS) of the scaffold were fixed while introducing amino moieties (R) on the lipophilic phenyl ring on the left-hand side (LHS) of the PBI core (figure 2). Upon identifying the moiety with the best balance of solubility and biological activity, the 4-OCF3Ph was replaced with various acyclic amino (SAR 2.3) while the CF3 was maintained on C-3 of the core scaffold. Finally, the CF3 was replaced with the 4-CF3Ph (SAR 2.4 and 2.5) while keeping fixed the optimal basic amine and the acyclic amino moieties on the LHS, respectively. Interestingly, the pursued structural modifications delivered analogues with a wide diversity of pharmacological and physicochemical properties. While some analogues demonstrated significant loss of pharmacological activity, others exhibited potent submicromolar antiparasitic activity (IC50 < 0.012 - 0.990 μM, PfNF54 and 0.360 - 0.850 μM, adult S. mansoni). Similarly, some analogues demonstrated poor solubility as low as < 10 μM while others demonstrated improved solubility as good as 180 μM.