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Synthesis of fluorinated drug scaffolds using SNAr substitution reactions

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posted on 23.11.2017, 09:29 by Yuqi Li
Fluorinated arenes are considered valuable in organic chemistry. They display different types of reactivity and physicochemical properties compared to their hydrogen analogues. In this project, our medicinal chemistry programme focused on developing rapidly accessible and modifiable heterocyclic scaffolds. Different classes of fluorinated heteroatom-containing organic compounds including benzothiophenes, (aza)phenoxazines and benzaldehyde phenylhydrazones were synthesised from highly fluorinated aromatic compounds with a diverse range of functional groups appropriate for medicinal chemistry development. Mechanistic studies for heterocyclic scaffold synthesis were discussed in the project. The mechanisms of the ring-forming reactions were elaborated in detail in each chapter. A range of substituents were introduced flexibly into the aromatic heterocycles, which were designed to meet the requirements for biological screening programmes. New compounds were characterized by 1H, 19F and 13C NMR spectroscopy, mass spectrometry and elemental analysis. The X-ray crystal structures of a fluorinated benzothiophene and two benzopyridooxazine derivatives were obtained confirming the structure and substitution pattern. From the heterocyclic scaffolds prepared, 6-benzimidazol-1-yl-benzothiophene derivatives (91), 3-imidazol-1-yl-pyridobenzoxazine derivatives (130) and 4-1-methylpiperazinyl-benzaldehyde phenylhydrazone derivatives (195) acted as hit compounds and demonstrated significant trypanocidal activities. SAR studies were employed in structural modifications on these samples to search for the best activities with highest selectivity.



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© Yuqi Li

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A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of Doctor of Philosophy of Loughborough University.