White Rose University Consortium logo
University of Leeds logo University of Sheffield logo York University logo

Design and synthesis of novel cytochrome bc1 inhibitors for the treatment of toxoplasmosis

Gordon, James Alexander (2018) Design and synthesis of novel cytochrome bc1 inhibitors for the treatment of toxoplasmosis. PhD thesis, University of Leeds.

[img] Text
Thesisfinal.pdf - Final eThesis - complete (pdf)
Restricted until 1 March 2024.

Request a copy

Abstract

Toxoplasmosis is a highly prolific and neglected disease, and current treatments fail to adequately address the challenges it presents. As such development of new more efficacious treatments, tailored to the complex nature of the infection, is required. The causative parasite Toxoplasma gondii is a resilient and resourceful organism, adept at invasion, avoidance and survival within its host. The cytochrome bc1 complex has been proven to be a validated target for the treatment of a number of apicomplexan parasitic diseases, including both malaria and toxoplasmosis. Recent work has also identified overexpression of this complex within a strain expressing the difficult to treat bradyzoite phenotype, which supported by findings that treatment with known bc1 inhibitor atovaquone shows reduction in cyst burden, suggests this may be a particularly promising target for an effective systemic parasite treatment. Within discusses the design, synthesis and analysis of a number of cytochrome bc1 inhibitors across several novel scaffolds. Designs focused on improving deficiencies identified in previous inhibitors. Successful synthesis of a number of these designs and biological evaluation identified several submicromolar examples. After preliminary ADMET evaluation of the synthesised scaffolds the tetrahydroquinolone scaffold was selected for further development. Optimisation of the synthesis to the tetrahydroquinolones (THQ’s) resulted in access to a library of analogues. From these analogues compound 169 was selected for further analysis, characterisation and ultimately progressed to early stage in vivo assays, in which it demonstrated exceptional potency and efficacy.

Item Type: Thesis (PhD)
Keywords: Toxoplasmosis,Toxoplasma gondii, cytochrome bc1, drug discovery
Academic Units: The University of Leeds > Faculty of Maths and Physical Sciences (Leeds)
The University of Leeds > Faculty of Maths and Physical Sciences (Leeds) > School of Chemistry (Leeds)
Depositing User: Mr James Alexander Gordon
Date Deposited: 07 Feb 2019 16:13
Last Modified: 07 Feb 2019 16:13
URI: http://etheses.whiterose.ac.uk/id/eprint/22638

Please use the 'Request a copy' link(s) above to request this thesis. This will be sent directly to someone who may authorise access.
You can contact us about this thesis. If you need to make a general enquiry, please see the Contact us page.

Actions (repository staff only: login required)