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Synthesis of Heterocyclic Compounds Using ketoacids-based Multicomponent Reactions and Evaluation of Their Anti-prion Activities

HSSKIA, AHMED MAJEED JASSEM (2018) Synthesis of Heterocyclic Compounds Using ketoacids-based Multicomponent Reactions and Evaluation of Their Anti-prion Activities. PhD thesis, University of Sheffield.

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Abstract

Prion disease is also known as transmissible spongiform encephalopathies (TSEs). They are incurable and fatal neurodegenerative diseases influencing both humans and animals. There is no effective cure for the TSEs currently available and this is of special concern in European countries. TSEs can be potentially represented as inherited, sporadic and iatrogenic. In this project a library of heterocyclic compounds synthesised was screened in scrapie cell line (SMB) hoping to find novel anti-prion lead compounds. The work outlined in this thesis consists of ten chapters: Chapter one contains a general introduction of heterocyclic compounds and their use in drug discovery. It also contains an overview of ketoacids chemistry, isocyanides and multicomponent reactions as efficient ways for synthesising diverse and various heterocyclic compounds. In addition, explains subject aims and objectives. Chapter two describes a method for the synthesis of keto acids, isocyanides and convertible isocyanide from cheap stating materials and the synthesis of cyclic amides (lactams) by multicomponent reactions (3C-4C-Ugi reaction). The methodology which depends on the activation of keto acids (Carboxylic group) using PPTS is an excellent route to accomplish Meyer’s lactamaztion in good yields. The optimisation and diastereoselectivity of all reactions are also discussed. Chapter three describes the synthesis of Ugi-tetrazole derivatives and information about using flow chemistry in this work. The results were investigated of similar reactions achieved using either batch or flow machines. Chapter four describes efforts towards using a microwave technique for synthesis a group of pyrazol-oxopyrrolidine derivatives with satisfactory yields. Chapter five includes an efficient methodology utilized to synthesize isoqunoline and isoindoline libraries from α-ketoacids and β-ketoacids in order to showcase the benefit of α- and β-ketoacids for synthesis of diverse heterocyclic compounds. Chapter six outlines exploiting post-transformations of multicomponent products for synthesis of diverse and various heterocycles with good yields. A central goal of further expansion is to provide collections of stereo chemically and structurally diverse compounds in order to evaluate their biological systems. The reaction of convertible isocyanide for synthesising pyroglutamic acid analogues is described. A developed method includes using bifunctional keto acids or amines via multicomponent reactions and their post-transformations for synthesis of tetrazole-lactams, diones, pyrrole-oxopyrrolidine and a set of medicinally-valuable pyrrolo-pyridine derivatives under mild conditions are also described. Chapter seven describes the main target of all synthesised compounds evaluated as anti-prion diseases. These compounds are designed to bind a putative binding pocket of PrPC and stabilise the normal isoform. This should prevent its conversion into the infectious isoform (PrPS) in brain. Chapter eight, nine and ten contain conclusion and future work, data of all experimental procedures and references respectively.

Item Type: Thesis (PhD)
Academic Units: The University of Sheffield > Faculty of Science (Sheffield) > Chemistry (Sheffield)
The University of Sheffield > Faculty of Science (Sheffield)
Depositing User: Mr AHMED MAJEED JASSEM HSSKIA
Date Deposited: 15 Oct 2018 09:07
Last Modified: 15 Oct 2018 09:07
URI: http://etheses.whiterose.ac.uk/id/eprint/21716

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