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Theses and dissertations (Applied Sciences)

Permanent URI for this collectionhttp://ir-dev.dut.ac.za/handle/10321/6

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Author: search.filters.author.Makhanya, Talent RaymondHas files: Yes

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    Synthesis, characterisation and biological activity of selected pyrazoles and naphthyrides
    (2019) Makhanya, Talent Raymond; Gengan, Robert Moonsamy
    The world continue to be threaten by various diseases from viruses, fungi and bacteria that cannot be cured. This arises due to the emergency of multidrug resistance in microorganisms hence current available drugs are becoming less potent. The solution to overcome this predicament is to further synthesize novel heterocyclic compounds which can display good therapeutic properties. Hence, this study focuses on the synthesis, characterization and biological evaluation of selected novel naphthyridinones, naphthyridines and pyrazoles. A total of 53 novel compounds were prepared by using multi-component reactions (MCRs), Povarov’s [4+2] and Povarov’s [3+2] reactions. The MCR was used for a solvent free synthesis of eight novel [1, 8] naphthyridinones from a mixture of 2-aminopicoline, various benzaldehyde derivatives and dimedone. A conventional heating protocol was used whilst the reaction was catalysed by phosphotungstic acid. The compounds were identified as 4, 8, 8-trimethyl-5- phenyl-5, 5a, 8, 9-tetrahydrobenzo[b] [1, 8] naphthyridin-6(7H)-ones with the aid of spectroscopic techniques, viz., FT-IR, NMR, EI- MS and elemental analysis. These eight compounds were screened for their anticancer activity against A549 lung cancer cells. Cell viability assays showed these compounds have a biological effect at various concentrations. Two compounds showed that good potential as an anti-proliferative agent and exhibited a dose- dependent decline in cell viability which was seen. The Povarov’s [4+2] cycloaddition reaction was used to synthesize nine novel fused indolo [1, 8] naphthyridines. Indole was used as the dienophile whilst N-aryl aldimines were selected as the diene which were produced by reacting 2-amino-4-picoline and benzaldehyde. The reaction was catalysed by indium chloride to produce 1-methyl-6-phenyl-6,6a,7,11b-tetrahydro-5H-indolo[3,2-c][1,8]naphthyridine which was characterized by FT-IR, NMR, TOF-MS and elemental analysis. Furthermore, all synthesized compounds were screened for their antimicrobial activity. The results of the bioassay demonstrated that some fused indolo [1, 8] naphthyridines exhibited good inhibitory effect with an MIC value ranging from 0.04687 to 0.09375 µM against Bacillus cereus and Staphylococcus aureus. The toxicity of the synthesized compounds were evaluated through mutagenicity test against Salmonella typhimurium TA 98 and TA100 strains. All compounds showed no mutagenic effects against Salmonella tyhphimurium TA 98 and TA 100 strains. The Povarov’s [3+2] cycloaddition was used to synthesize twenty six novel fused indolo pyrazole in the presence of a catalytic amount of indium chloride. The compounds were identified as 3- phenyl-2, 3-dihydropyrazolo [3, 4-b] indole-1(4H)-carbothioamides with the aid of spectroscopic techniques such as FT-IR, NMR and TOF-MS. All compounds were screened for their antimicrobial activity against various strains of pathogenic bacteria and fungi. These compounds showed good activity against Candida albicans, Candida utilis, and Saccharomyces cerevisiae with MIC of 1.5; 1.1 and 0.375 µM respectively. In addition, all the compounds showed no mutagenic activity against Salmonella tyhphimurium TA 98 and TA100 strains. The scope of the Povarov’s [3+2] reaction was further investigated using isoniazid to synthesise ten novel nicotinyl fused indolo pyrazoles in the presence of a catalytic amount of indium chloride. These compounds were identified as (3-phenyl-2,3- dihydropyrazolo[3,4-b]indol-1(4H)-yl)(pyridin-4-yl)methanone with the aid of spectroscopic techniques such as FT-IR, NMR and TOF-MS. All compounds were screened for their antimicrobial activity against various strains of pathogenic bacteria and fungi. The synthesized compounds showed weak activity against Streptococcus faecalis, Micrococcus luteus and Bacillus coagullans with a zone inhibition diameter of 9 mm and MIC of 0.75 µM. Furthermore, all synthesized compounds were tested for their toxicity against Salmonella tyhphimurium TA 98 and TA100 strains: none showed mutagenic activity.
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    Synthesis of bisquinolines through conventional and unconventional energy sources
    (2011) Makhanya, Talent Raymond; Gengan, Robert Moonsamy
    Malaria, the most prevalent parasitic disease, is considered a neglected disease owing to insufficient research and development in synthesis and therapy worldwide. Therapy failures are frequent and are due to a variety of factors such as the intrinsic characteristics of the disease, conditions of transmission, and the difficult control of spreading through tropical areas. Primary factors are the complexity of the parasite life cycle and the development of drug resistance. Another critical factor is the increasing number of immune-compromised patients that suffer from malaria and human immunodeficiency virus (HIV) co-infections. Most of the drugs currently available to treat malaria are quinoline derivatives modelled on the quinine molecule, found in the bark of Cinchona trees. Over the last 50 years the use of quinine has declined owing to the development of synthetic 4-aminoquinolines such as chloroquine. However, the malaria parasite is rapidly becoming resistant to the drugs currently available. Recently bisquinoline compounds were found more potent than chloroquine against both chloroquine-sensitive and resistant strains of malaria; this improved efficacy and prompted an increased interest in the design of these anti-malarial drugs. Although several synthetic methods are available to synthesise bisquinolines, we report the synthesis of bisquinolines from simple, readily available and cost- effective starting compounds. The synthesis was accomplished in four reaction steps using the Claisen condensation, Vilsmeir-Haack reaction, formation of a Schiff base and thermal cyclization, sequentially. We used a conventional energy source and microwave irradiation for the synthesis, wherever possible, of 2, 4-dichloro-3, 4'-biquinoline and 2, 4-dichloro-7'-methoxy-3, 4'-biquinoline. In the first step, 3-acyl-2, 4-dihydroxyquinoline is synthesised from an equimolar mixture of methyl-2-aminobenzoate and ethyl acetoacetate by microwave irradiation for 3 minutes; the yield is 90 % whereas by 6 hours refluxing the yield is 75 %. This is followed by the synthesis of 3-chloro-3-(2,4-dichloroquinolin-3yl) acrylaldehyde, by combining DMF and POCl3 at 00C to form the electrophile which reacts with 3-acyl-2,4-dihydroxyquinoline under microwave irradiation for 5 minutes; the yield is 65 % whereas by 6 hours refluxing the yield is 50 %. In the next step, several protocols to prepare a Schiff base 3-chloro-3-(2, 4-dichloroquinolin-3-yl) allylidene aniline are investigated with the best yield of 75% obtained by microwave irradiation for 5 minutes. Subsequently three aniline derivatives viz, 4-methoxyaniline, 4-chloroaniline and 4-methylaniline, are used as substrate to prepare 3-chloro-3-(2,4-dichloroquinolin-3-yl) allylidene-4-methoxyaniline, 3-chloro-3-(2 ,4-dichloroquinolin-3-yl) allylidene-4-methylaniline and 3-chloro-3-(2, 4-dichloroquinolin-3-yl) allylidene-4-chloro aniline at 68, 78 and 64 % yield, respectively. In the final step, 2, 4-dichloro-3, 4'-biquinoline is prepared; several methods were investigated, however, the best yield is 24 % which is obtained under alkaline conditions in the presence of K2CO3 and DMF by microwave irradiation for 10 minutes. The 2, 4-dichloro-7'-methoxy-3, 4'-biquinoline derivative is also prepared in 18 % yield under the same alkaline conditions. The outline of the total synthesis of bisquinoline is presented graphically below.