Novel synthetic methodology for the assembly of a-carbolines and 7-azaindoles

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dc.contributor.authorHenning, Hendrik
dc.date.accessioned2018-10-09T07:27:55Z
dc.date.available2018-10-09T07:27:55Z
dc.date.issued2018
dc.descriptionA thesis submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Doctor of Philosophy Johannesburg, February 2018en_ZA
dc.description.abstractThe a-carbolines and 7-azaindoles are part of a larger family of compounds derived from indoles and other heterocyclic compounds that are prevalent in nature often as biologically active compounds. The synthesis of a-carbolines and 7-azaindoles described in this thesis is built on several key reactions developed in our laboratories, namely the light mediated t-BuOK ring closure method used previously to form carbazoles, naphthalenes and anthracenes; as well as an acid mediated ring closure of acetylene containing 2- aminopyridines to form 7-azaindoles; and lastly catalytic palladium chemistry is used in some critical carbon carbon bond forming reactions, namely through the Sonogashira reaction. The bromine atoms on several 3-bromo-2-aminopyridine compounds is substituted with 1-ethynyl-2-methyl-benzene in a Sonogashira coupling reaction, followed by ring closure forming the respective 2-(2-methylphenyl)-1H -pyrrolo[2,3-b]pyridines (2-(o-tolyl)-1H -7- azaindoles). After formylation on the 3 position, forming 2-(2-methylphenyl)-1H -pyrrolo [2,3-b]pyridine-3-carbaldehydes (3-formyl-2-(o-tolyl)-1H -7-azaindoles), and N -benzylation on the 1 position, furnishing 1-benzyl-5-methyl-2-(2-methylphenyl)-pyrrolo[2,3-b]pyridine -3-carbaldehydes (3-formyl-2-(o-tolyl)-1-benzyl-7-azaindoles), the compounds were subjected to the light mediated ring closing methodology described, yielding 11-benzyl-benzo -a-carbolines (11-benzyl-11H -benzo[g]pyrido[2,3-b]indoles). The final debenzylation on 11-benzyl-benzo-a-carbolines (11-benzyl-11H -benzo[g]pyrido[2,3-b]indoles) synthesised furnished 11H -a-carbolines (11H -benzo[g]pyrido[2,3-b]indole). The novel synthesis of a-carbolines and 7-azaindoles through these methods proved successful, even though in low overall yields. The methodology was further extended to allow further substitution on a-carbolines. This was achieved by bromination on the initial 2-aminopyridine starting material in the 5 position, followed by iodination on the 3 position. The iodide of the 2-aminopyridine could then be selectively substituted using Sonogashira coupling as discussed, followed by Suzuki coupling on the bromide, in this case with 3,4- dimethoxy-phenyl boronic acid. The synthesis of 11H -3-(3,4-dimethoxyphenyl)-benzo-a- carboline was then completed using Suzuki coupling methodology to add the 3,4-dimethoxyphenyl functionality from (3,4-dimethoxyphenyl)boronic acid. The heterocycles synthesised in this thesis were tested against African sleeping sickness parasite Trypanosoma brucei. The compound 5-(3,4-dimethoxyphenyl)-2-(2-methylphenyl) -1H -pyrrolo[2,3-b]pyridine-3-carbaldehyde was found to have an IC50 value of 10 mM, with several others showing activity in the range of 12-27 mM. The antimalarial studies in contrast showed only one significant hit, 11-benzyl-3-(3,4dimethoxyphenyl)-benzo- a-carboline had an IC50 value of 26 mM. Overall, the study resulted in the successful synthesis of a-carbolines and 7-azaindoles, as well as the discovery of biologically active heterocycles effective against malaria and African sleeping sickness. These heterocycles could be used as lead compounds for further research.en_ZA
dc.description.librarianMT 2018en_ZA
dc.format.extentOnline resource (xi, 199 leaves)
dc.identifier.citationHenning, Hendrik (2018) Novel synthetic methodology for the assembly of a -carbolines and 7-azaindoles, University of the Witwatersrand, Johannesburg, <http://hdl.handle.net/10539/25742>
dc.identifier.urihttps://hdl.handle.net/10539/25742
dc.language.isoenen_ZA
dc.subject.lcshCarbolines
dc.subject.lcshNeurotoxic agents
dc.titleNovel synthetic methodology for the assembly of a-carbolines and 7-azaindolesen_ZA
dc.typeThesisen_ZA
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