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Title: Design and synthesis of N-Myristoyltransferase inhibitors : a promising treatment for malaria
Author: Rackham, Mark
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Diseases caused by parasitic infections such as malaria represent a huge global health burden, and new therapies are in great demand. N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme important for multiple processes in vivo, and represents an attractive drug target to combat Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) infections. This work describes the development of NMT inhibitors from hit generation to lead development, and is divided into six chapters: Chapter 1 provides an introduction to malaria and NMT, as well as the history of NMT as an anti-infective drug target. This chapter also provides evidence of the utility of NMT as a drug target in malaria. Chapter 2 describes the generation of a hit series of plasmodial NMT inhibitors. Starting from a previously described PfNMT inhibitor, a 'lead-hopping' strategy based on crystallographic information and aromaticity yielded a series of novel, selective and ligand efficient inhibitors of plasmodial NMT. Chapter 3 details the hit-to-lead development of this series. Crystallography facilitated the removal of a potentially labile ester, resulting in an improved pharmacokinetic profile. Subsequent optimisation based on lipophilicity yielded a potent plasmodial NMT inhibitor, with antiparasitic activity in vitro that correlates to intracellular NMT inhibition. Chapter 4 is an account of the efforts made to modify the physicochemical properties of the series, thereby modifying the translation from enzyme to cellular assays. This work established that the pKa of the inhibitors is unlikely to be the sole reason for poor cellular translation. Chapter 5 provides a summary of the work described throughout this thesis, as well as future work. This future work will facilitate the development of the compounds described in this work into a late-lead series, progressing towards a clinical candidate NMT inhibitor for the treatment of malaria. Chapter 6 contains experimental details and analysis for all work described herein.
Supervisor: Leatherbarrow, Robin Sponsor: Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available