Theses and dissertations (Applied Sciences)
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Item Synthesis, characterisation and biological activity of selected pyrazoles and naphthyrides(2019) Makhanya, Talent Raymond; Gengan, Robert MoonsamyThe 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.Item Microwave as an energy source in the synthesis of 2-aryl-4-quinolone alkaloids and naphthyridines(2011) Ndaba, Hlengiwe Glenrose; Gengan, Robert MoonsamyOne of the greatest medical challenges facing mankind is the Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) which has now become a major epidemic with more than 40 million people infected worldwide. Of equal concern is its implication in high mortality and the onset of a number of opportunist mycobacterial infections, principally tuberculosis. In spite of the discovery of some relatively effective antiretroviral (ARV) drugs such as Azido Thymidine (AZT), Nevirapine (NVP) and Efavirenz (EFV), its’ application as either a single or combinational form causes side effects by harming the bone marrow. Drug resistance is a key cause of failure for treatment of HIV infection. Hence greater interdisciplinary efforts, involving both natural and social sciences, are needed urgently to combat this HIV/AIDS pandemic. Heterocyclic nitrogen based compounds, obtained from either natural sources or synthesis are adequately documented to have increased biological activity against several diseases. Recently a study of drugs containing the naphthyridine scaffold has acquired increasing attention because of its potential against HIV/AIDS. Generally, naphthyridines demonstrate good potency in both the enzyme and cellular systems and this prompted our interest in the synthesis of naphthyridine derivatives from simple and readily available starting compounds. Furthermore we wanted to form an intermediate quinolone moiety since it has good biological potential. In this study we report the synthesis of three naphthyridine derivatives, i.e. 6-phenyl-dibenzo [b, h] [1, 6] naphthyridine, 4-methyl-6-phenyl-dibenzo [b, h] [1, 6] naphthyridine and 2- methyl-6-phenyl-dibenzo [b, h] [1, 6] naphthyridine from easily available chemicals such as aniline, ortho-toludine, para-toluidine and ethyl benzoylacetate via a five step reaction scheme using either conventional reflux, microwave irradiation or both methodologies. It was found that microwave irradiation was several folds faster than conventional reflux methodology and the yield of the product was higher. The first step of the reaction scheme is a simple condensation reaction: three acrylate derivatives, viz. ethyl-3-aniline-3-phenyl acrylate, ethyl-3-phenyl-3-(ortho-tolylamino) acrylate and ethyl-3-phenyl-3-(para-tolylamino) acrylate were synthesized by refluxing ethyl benzoylacetate in an acidified ethanolic solution with aniline, ortho-toluidine and paratoluidine respectively for three hours; the yields were 95, 87.5 and 80 % respectively. Page v In the second step, thermal cyclisation was achieved for the synthesis of three quinoline derivatives, viz. 2-phenylquinoline-4(1H)-one, 8-methyl-2-phenylquinoline-4(1H)-one and 6- methyl-2-phenylquinoline-4(1H)-one from their respective acrylates under microwave irradiation for 5 minutes at 180 °C and 250 watts; the yields were 92, 84 and 80 % respectively. In the third step of the reaction, synthesis of 4-chloro-2-phenylquinoline, 4- chloro-8-methyl- 2-phenylquinoline and 4- chloro-6-methyl-2-phenylquinoline was achieved from a mixture of POCl3 and their respective quinolines via microwave irradiation for 3 minutes at 75 °C and 150 watts and via conventional reflux for 5 hours. It was found that under microwave irradiation, the reaction occurred nearly 100 fold faster but the % yield of the product was marginally higher. The fourth step of the reaction resulted in the formation of three schiff’s base, viz. 4-(Nphenyl)- 2-phenyl-4-aminoquinoline, 8-methyl-4-(N-phenyl)-2-phenyl-4-aminoquinoline and 6-methyl-4-(N-phenyl)-2-phenyl-4-aminoquinoline from their respective quinolines via microwave irradiation for 20 minutes at 180 °C and 180 watts and via conventional reflux for 2 hours. It was found that under microwave irradiation, the reaction occurred nearly 6 fold faster and the % yield of the product was over 10 % higher. The final step of the reaction was achieved by a Vilsmeir Haack reaction and in situ base catalyzed thermal cyclisation: 6-phenyl-dibenzo [b, h] [1, 6] naphthyridine, 4-methyl-6- phenyl-dibenzo [b, h] [1, 6] naphthyridine and 2-methyl-6-phenyl-dibenzo [b, h] [1, 6] naphthyridine were synthesized from their respective schiffs base via microwave irradiation for 20 minutes at 75 °C at 120 watts and via conventional reflux for 21 hours. It was found that under microwave irradiation, the reaction occurred over 60 fold faster and the % yield of the product was over 20 % higher.The outline for the five step synthesis of the three naphthyridines is presented graphically below: Page vi Key: (a) R1= H; R2=H (b) R1 = H; R2 = CH3 (c) R1 = CH3; R2 =H Reaction Conditions: 1) conc.HCl, EtOH, 3hrs, 50 °C; 2) conc. HCl, hand stirring 10 min; 3) 180 °C, MWI, 250 watts, 5 min; 4) POCl₃, MWI, 75 °C, 150 watts, 2 min; 5) POCl₃, 100 oC, 5 hrs; 6) aniline, t-BuOH, MWI, 180 °C, 180 watts, 20 min; 7) aniline, t-BuOH, 80 °C, 3 hrs; 8) DMF, POCl₃, MWI, 75 °C,120 watts 20 minute; 9) DMF, POCl3, 100 oC, 21 hrs.