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Synthesis and functionalisation of heterocyclic molecules with bioactive properties

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Hyland, IKP ORCID: 0000-0001-9850-0238 2020 , 'Synthesis and functionalisation of heterocyclic molecules with bioactive properties', PhD thesis, University of Tasmania.

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Abstract

Heterocycles are one of the most important class of molecules in medicinal chemistry. These compounds comprise a vast amount of the bioactive molecules available and provide biological activity over a huge range of targets. This work strives to develop novel drug candidates to target different diseases, utilising structure-activity relationship data and the results of biological testing to guide synthesis. The ultimate aim is to discover lead drug candidates that could advance to clinical trials and are readily accessible.
Part One of this thesis discusses the synthesis of thiophenes and preliminary studies investigating their capacity to act as PAF receptor antagonists. More than 40 diseases and disorders are associated with the inflammatory actions of PAF and its receptor. Antagonists can be used to control these inflammatory responses. Existing antagonists suffer from difficult and lengthy syntheses. A range of 2-pyrrolothiophenes were prepared via an efficient 2-step pathway. A number of these analogues showed excellent activity and potency as PAFr antagonists in vitro, with no toxic effects observed in initial tests up to concentrations of 100 μm.
A range of thienoquinolines were also synthesised, via a rapid and highly efficient route. In preliminary in vitro results, a number of these new molecules have exhibited selective and potent anti-giardial activity (<5 μg/mL) and complete inhibition of growth. Giardia intestinalis is a common protozoan parasite which infects the intestines of various mammals, causing giardiasis. In 2004, Giardiasis was classified as a Neglected Disease by the World Health Organization (WHO). It affects about 280 million people annually, and for developing countries, diarrheal disease is the leading cause of death for children younger than five years of age. New antimicrobial drugs are necessary to stay ahead of the emerging resistance to existing antimicrobial therapies, which is an ongoing and significant issue in up to 20% of cases.
Part Two of this thesis investigates the mode of action of quinone compounds in the rescue of ATP production associated with mitochondrial dysfunction. The prevailing wisdom is that these quinone molecules act as electron shuttles in the electron transport chain (ETC) and, hence, need to be redox-active. A new range of redox-inactive molecules were prepared to explore whether a non-redox mode of action may be operative. These molecules were found to be inactive, with no improvement in ATP production compared to the control. This strongly supported the hypothesis that these molecules do need to be redox active and participate in the electron transport chain.
Part Three of this thesis concerns the investigation of the chlorinated heterocycle CDMT (2-chloro-4,6-dimethoxy-1,3,5-triazine) as a new reagent for N-demethylation. N-Demethylation is an important step in the late-stage functionalisation and semi-synthesis of various opioids. For opiates, many methods exist for N-demethylation, but are often compound-specific, and have various drawbacks that include the use of toxic reagents, harsh reaction conditions, incompatibility with functional groups or the necessity to use protecting groups, poor efficiency, and formation of side products. For non-opioid N-demethylations, selectivity is the biggest issue.
CDMT is a reagent traditionally used for peptide coupling reactions but has been observed to demethylate N-methyl morpholine via an N-heterocyclic intermediate. This reactivity prompted an investigation into the application of CDMT as a new demethylating agent. Initially, the reagent was successfully applied to alkaloid-type compounds such as codeine in THF, acetonitrile, or neat. The identity of the solvent was found to be important, as many substrates did not react in dichloromethane but formed demethylated products in ethanol. Both opioid and non-opioid substrates have been successfully reacted with CDMT, but results indicated that a secondary pathway was in competition, causing varied results depending on the substrate used.

Item Type: Thesis - PhD
Authors/Creators:Hyland, IKP
Keywords: Heterocycles, Synthesis, Medicinal chemistry, PAF
DOI / ID Number: 10.25959/100.00035032
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Copyright 2020 the author

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