Saudi Cultural Missions Theses & Dissertations
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Item Restricted Design, synthesis and SAR evaluation of Antituberculosis Agent.(Newcastle University, 2024-06) Alsalem, Fatimah; Sellars, JonThere is an urgent need to discover and develop novel therapeutic alternatives for treatment of Mycobacterium tuberculosis (Mtb) infection, especially for infections caused by drug-resistant strains, to mitigate the global burden of tuberculosis disease. Initially within our group, a benzoxa-[2,1,3]-diazole moiety was employed in these investigations; however, the group has recently adopted a scaffold hopping strategy to generate several structurally diverse examples while maintaining antitubercular efficacy, often enhancing antitubercular activity. The pharmacophores imidazo[1,2 a]pyridine and 3,5-dinitrobenzene N-amino acid substituted hydrazides are of particular interest. The results for imidazo[1,2 a]pyridine substituted amino acid hydrazide compounds demonstrated increased activity with unsubstituted side chains on the amino acid and variable activity depending on the position of the halogen in the aromatic hydrazine. Furthermore, compared to the prior series, the results showed a higher level of action against bacteria with the 3,5-dinitrobenzene moiety substituted amino acid hydrazide, indicating the potential utility of these compounds as future antitubercular medications. Furthermore, this research was conducted to explore the coupling of the N-amino acid hydrazide structure with a scaffold comprising a one nitrogenous group in Pretomanid and 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl). Unfortunately, these attempts were not successful, but it is worthwhile considering modifications for future endeavours.15 0Item Restricted Phthalocyanine hybrids; old chemistry revisited and new syntheses(University of East Anglia, 2024-05-28) Farhan, Nora; Cammidge, AndrewThe work described in this thesis is concerned with the investigation of synthetic pathways toward tetrabenzoporphyrin/phthalocyanine hybrid macrocycles, specifically tetrabenzomonoazaporphyrins (TBMAPs) or other less-nitrogenous hybrids. The initial investigation was conceived to modify the latest synthetic procedure developed in the Cammidge group whereby utilisation of a less nitrogenous precursor (alkynylbenzonitrile, 1 x N) replaced phthalonitrile (2 x N) as co-macrocyclisation partner with an aminoisoindoline. Unfortunately, no hybrids were formed and instead the formation of a six- membered ring isoquinoline from the acetylene was observed under these conditions. Linstead’s method to synthesise TBMAPs was then revisited, and different malonyl aminoisoindolines were synthesised and isolated. These precursors proved to be unstable under many conditions which resulted in the formation of their keto-esters and dimers during their purification process. Fusion of these precursors with zinc dust at 220oC proved to give a mixture of hybrids but no evidence for the expected TBMAPs’ formation, according to MALDI-MS analysis. Isolation of the hybrids was challenging and complicated by slow decomposition during chromatography. We switched to investigate Linstead’s conditions of fusion in the presence of zinc metal at high temperature on our proposed reactants (alkynylbenzonitrile with aminoisoindoline) and, interestingly, formation of ZnTBTAP, cisTBDAP, transTBDAP and traces of ZnTBMAP were observed. However, the formation of these hybrids proved to be a result of macrocyclisation of one reactant only – the aminoisoindoline. Full analysis of all hybrids was obtained, except ZnTBMAP due to its low quantity. In the final part of the thesis, we further explored the latest Cammidge procedure to synthesise TBTAPs by employing substituted phthalonitriles (“B”) with aminoisoindolines (“A”), in this case using different metals to track the origin of each unit in the final TBTAPs. ABBB TBTAPs were selectively obtained in high yield when zinc chloride was utilised while a mixture of ABBB and ABBA TBTAPs were obtained when different metals were employed. Full characterisation of the obtained hybrids and intermediates was achieved. The formation of these hybrids is somewhat surprising and no obvious mechanisms for their formation are apparent.17 0Item Restricted Design and Synthesis of Luminescent probes aimed at biologically important targets(Cardiff UniversityCardiff University, 2024-06-13) Alenazy, Deemah Mizher; Pope, SimonThis thesis further developed the synthesis of numerous novel fluorescent functionalised species and provided in-depth analyses of their photophysical characteristics and potential for use in imaging, sensing, and therapeutic applications. In Chapter 2, the approach aimed to develop the synthetic chemistry of a wide range of novel fluorescent functionalised naphthylamide species containing piperazine binding site. Then investigations were completed into the chemistry of these species with the cholesterol conjugates species. A series of cholesterol functionalised naphthylamide was successfully completed. Once synthesised it was intended for cholesterol species to be spectroscopically and analytically characterised. This provided data indicating their synthesis with spectroscopic studies being particularly important for characterising the compounds and their electronic properties. Chapter 3 has described the synthesis, structural, and spectroscopic properties of a variety of mono- and disubstituted anthraquinone species containing various substituted amines. A number of biological studies, including cytotoxicity assessment, were conducted on selected AQ species. The presence of various amine groups on the AQ core has a significant impact on biological behavior. Chapter 4 described the synthesis of the new substituted aza-anthraquinone series, which yielded eight new species. The structural variants attempt to strike a balance between hydrophilic and lipophilic properties. The photophysical data displaying emission properties in the red region with favourable characteristics towards potential cell imaging applications clearly shows that the species discussed herein are clearly interested. Chapter 5 describes the successful synthesis of four photoactive compounds containing both anthraquinone and naphthalimide fluorophores. Nature of the linking amine unit differs between the species. The dual NAP-AQ core's design allows the physical properties to be tuned to a high degree of functionality. The species covered in this chapter are undeniably intriguing, and photophysical data show intense emission characteristics that might be useful for cell imaging applications.34 0Item Restricted Synthesis of a di-porphyrin molecular cage(Saudi Digital Library, 2023) Alharbi, Mona; Cammidge, Andrew NPorphyrins and their derivatives are highly stable macrocyclic compounds with extended 𝜋-network that play crucial roles in different life forms. Inspired by the important roles of porphyrins in nature, molecular scientists have deployed both natural and synthetic analogues of porphyrins and their metal complexes in different areas of applications including biomimetic, single molecule magnet, molecular switches, nanoreactors, photodynamic therapy and molecular information storage. This work describes synthesis of a metal-free di-porphyrin molecular cage that was designed and synthesised via triple-decker lanthanum porphyrin-phthalocyanine porphyrin intermediate. This triple-decker intermediate was assembled by previously described methods with functionalised linkers that were cross-linked by olefin metathesis using Grubbs catalyst. Attempt to demetallation this triple-decker cage using different acid-treatments to obtain the desired dimeric porphyrin molecular cage with phthalocyanine guest yielded different results. Reaction of the triple-decker cage with H2SO4 and trifluoroacetic acid respectively gave a di-porphyrin molecular cage, while treatment with acetic acid led to removal of one of the lanthanum ions. The intermediate triple-decker and the synthesised free di-porphyrin molecular cage have been characterised by 1H and 13C NMR, MALDI-ToF-MS, UV-visible absorption spectroscopy and X-ray crystallography.23 0Item Restricted Altering the Morphological Properties of Nano-Scale Hydroxyapatite Via Sol-Gel Synthesis.(Saudi Digital Library, 2023-11-03) Alnasr Allah, Fahad; Miller, Cheryl; Harrison, Caroline; Joshi, ShivaniBackground: Bone defects and infections are significant clinical challenges facing maxillofacial and orthopaedic surgeons. These conditions can arise from trauma, cancer or infections, leading to bone tissue loss and structural changes requiring intervention and treatment. Traditional approaches to bone regeneration and infection management have limitations (e.g., immunological rejection by the host, transmission of diseases and costs); this highlights the need for innovative solutions to overcome the clinical obstacles associated with traditional treatment of bone defects. Nano-hydroxyapatite biomaterials have shown promising effects when used as bone graft substitutes because they promote bone tissue growth, making them candidates for addressing bone defects. Materials and Methods: Nano-scale hydroxyapatite was synthesised via the sol-gel method, three with different stirring speeds overnight and the fourth batch with 5 g of 3-Aminopropyltriethoxysilane (APTES) stirred at medium stir speed overnight. After that, the supernatant was poured off, and the nHA was washed until the conductivity was stable. The suspensions were dried to a powder (for characterisation) in the oven at 60°C overnight. The samples were characterised using x-ray diffraction (XRD) to identify the crystal phases, transmission electron microscopy (TEM) to image the particle shapes and zeta potential to analyse the surface charge. Results: All samples were successfully crystallised based on the XRD results. The main crystal phase of all the experimental samples was identified precisely and matched those specified in (pure hydroxyapatite, JCPDS card #09-0432), but the samples prepared had a lower degree of crystallinity than the ReproBone® novo. In addition, the stirring speed and/or the addition of APTES affected the size, morphology, particle aggregate and surface charge. Conclusion: Within the study's limits, it was concluded that the difference in the stirring speeds and/or the addition of APTES affect intense crystallisation. In addition, that affects the size, morphology, aggregate of particles and the surface charge of the particles. Thus, knowing the causes and effects of these changes may contribute to the synthesis of HA with better biocompatible and mechanical properties.25 0Item Restricted Optimization Of Enantiopure Tetrahydro-Β-Carbolines as Potent Antimalarials & Exploration of Salicylic Acid Analogs for Combating Multidrug-Resistant Neisseria Gonorrhoeae(2023-05-13) Almolhim, Hanan; Carlier, PaulThe emergence of drug resistance towards existing drugs is a constant challenge in the fight against many diseases including Malaria and gonorrhoeae. To evade resistance, new targets must be engaged, and to do that, new structural classes of anti-infective must be prepared and evaluated. During the course of my PhD journey, I had the opportunity to investigate and optimize the antimalarial candidate (Å})-2-3b, and salicylic acid (4-1a) as an anti-gonorrhea treatment. Malaria is a life-threatening mosquito-borne disease. In 2021, there were 247 million cases of malaria and the estimated number of malaria deaths stood at 619,000. Because of the rapid development of resistance to all current antimalarials, discovery of antimalarials with unexploited mechanisms of action is critical to reduce malaria mortality. In the Carlier group, our initial approach focused on discovery of inhibitors of the methylerythritol phosphate (MEP) pathway for isoprenoid precursor biosynthesis, since this pathway is essential for Plasmodium falciparum and absent in human. Application of the isopentenyl pyrophosphate (IPP) chemical rescue screen to the compounds of the Malaria Box, a collection of 400 antimalaria candidates with unknown mechanisms of action, identified tetrahydro-β-carboline 2-1 (MMV008138) as an inhibitor of the MEP pathway. Chapter 2 of this work discusses similarity searching of the Novartis portion of the hit set (5K compounds), from the original 20K compound hit set of the Malaria Box, and identifying tetrahydro-β-carboline GNF-Pf-5009, designated as (Å})-2-3b. Preparation of pure enantiomers, by resolution, demonstrated the pharmacological superiority of (R)-2-3b over (S)-2-3b, which was ound to have good asexual blood stage (ABS) inhibition potency against malarial parasites P. falciparum, and low general cytotoxicity. However, (R)-2-3b was found not orally efficacious in a P. berghei mouse model of malaria. We concluded that the lack of oral efficacy of (R)-2-3b was due to its poor drug-like qualities, in particular its high molecular weight and low solubility. Chapter 3 of this work explores modifications of (R)-2-3b ((R)-3-5Aa) that were expected to improve its properties. We show that the new compounds (R)-3-5Gm and (R)-3-5Gk not only are more potent in vitro than (R)-2-3b ((R)-3-5Aa), but also have molecular weights < 500 g/mol. Neisseria gonorrhoeae is the causative agent of the sexually transmitted disease gonorrhea. Due to the increased rates of infection as well as the prevalence of multidrug-resistant N. gonorrhoeae strains worldwide, the World Health Organization (WHO) and the U.S. Centers for Disease Control and Prevention (CDC) list N. gonorrhoeae at the highest possible threat level to public health. Dual therapy of azithromycin (AZM) and ceftriaxone has been the standard-of-care for treatment of gonococcal infections. However, due to increasing resistance to azithromycin (>33% in some regions) the CDC removed AZM from the treatment regimen for gonorrhea in 2020. Therefore, ceftriaxone remains the only recommended antibiotic for treatment of gonococcal infections. However, increasing resistance to this treatment option has been reported, consequently there is an urgent need to identify novel therapeutics against N. gonorrhoeae. Drug repurposing is a popular strategy that explores new therapeutic opportunities for approved drugs with available information on their pharmacokinetic data, dosages, and toxicity. Salicylic acid is a highly privileged chemical scaffold. Also, the use of salicylic acid to treat sexually transmitted diseases (including gonorrhea) was reported as early as the 19th century. Recently, Dr. Mohamed N. Seleem reported that salicylic acid (4-1a) exhibited modest activity against N. gonorrhoeae strains including the AZM-resistant strain (CDC-181). Chapter 4 of this work illustrates how the anti-gonococcal activity in this scaffold is easily lost by inopportune substitution. However, we found that substituted naphthyl analogs (4-3b,o,p) have superior activity to salicylic acid itself. In addition, the three analogs showed high selectivity, compared to AZM, against N. gonorrhoeae over the vaginal microbiota.15 0