Hydrogen peroxide and hydrohalic acid mediated synthesis of halogenated benzimidazolequinones and anti-cancer evaluation of benzotriazinones
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Chapter 1 provides a literature review of metal and metal-free oxidative annulations employed to access ring-fused benzimidazoles while highlighting their significance and application towards anti-tumour benzimidazolequinones. The aims and objectives of the thesis are included at the end of this Chapter. Chapter 2 starts with a review detailing the green credentials of H2O2, EtOAc, and methanesulfonic acid (MSA) with an emphasis on the sustainability of their production. Pyrrolo[1,2-a]benzimidazoles were prepared from o-pyrrolo substituted anilines using H2O2 in EtOAc, avoiding the traditional use of carboxylic acid solvents. The protocol circumvented aqueous extraction and chromatography, and could be applied to six, seven, and eight-membered cyclizations. Pyrido[1,2-a]benzimidazole formation and the cyclization of 3,6-dimethoxy-2-(cycloamino)anilines required one equivalent of MSA in order to achieve high yields. Chapter 3 starts with a review discussing the impact of carbon-halogen bonds in medicinal chemistry, H2O2/HX as a benign method for the synthesis of halogenated heterocycles, and current methods to form p-quinones. The one-pot tunable protocol of H2O2/HX can be used to either perform 4-electron or 6-electron oxidation to access dimethoxy ring-fused benzimidazoles, as well as chlorinated and brominated ring-fused benzimidazolequinones in high yields. HPLC reaction profiling indicated that halogenation occured prior to oxidative cyclization. Cl2 and Br2 were determined as active species in the one-pot reactions. H218O labeling experiments on dimethoxy benzimidazoles provided insight into the mechanism of ether cleavage. The nitration of 2-fluoro-1,4-dimethoxybenzene formed exclusively 1-fluoro-2,5-dimethoxy-4-nitrobenzene. Chapter 4 starts with a brief description of subject heterocycle synthesis, the National Cancer Institute Development Therapeutic Program (NCI-DTP), thioredoxin reductase (TrxR), and defines the different types of reversible enzyme inhibition. The in-house cytotoxicity evaluation of a series of benzo[1,2,4]triazin-7-ones is described. COMPARE analysis at the NCI showed a very strong correlation between 1,3-diphenylbenzo[1,2,4]triazin-7-ones and pleurotin. The latter natural antibiotic is an irreversible TrxR inhibitor. Enzyme assay data were analysed using the Lineweaver-Burk plot, which confirmed that 1,3-diphenylbenzo[1,2,4]triazin-7-one and the 3-CF3 substituted analogue are reversible TrxR inhibitors. The latter is more potent displaying uncompetitive inhibition, rather than the mixed inhibition of the parent compound.