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Title: New and established drug targets for malaria chemotherapy from lead optimisation of 2-pyridyl quinolone PfNDH2 inhibitors to semi-synthetic pyrrole Mannich base artemisinin derivatives
Author: Leung, Suet Ching
ISNI:       0000 0004 2745 6382
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2012
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The rapid development of resistance to currently deployed antimalarial drugs has raised the desperate need for new chemotherapies, preferably with novel therapeutic target. This thesis explores the synthesis of novel quinolone compounds and artemisinin derivatives targeting the mitochondrial electron transfer chain (ETC) and the haemoglobin degradation of Plasmodium falciparum respectively. The respiratory chain of the human malaria is an attractive target for antimalarial drugs. It is believed that the collapse of the mitochondrial potential will shut down the metabolism and malaria parasite de novo synthesis of pyrimidines, ultimately leading to the death of parasite. The bc1, (Complex III) inhibitors are being studied by many scientists, with recent studies targeting PfNDH2 due to its potential as a therapeutic target (Humans lack this enzyme in the respiratory chain). Following the hit to lead optimisation of chemical name here CK-2-68 against the PfNDH2 enzyme in the group, a series of quinolones were designed to improve the ClogP and aqueous solubility. Analogues in this series were synthesised in less than six-step. Our strategy for reducing the ClogP of the original series involves the incorporation of heterocycles into the C and 0 rings of the side chain. Work describes in this thesis was principally cover the 2-pyridyl series of compounds. Two of these analogues have ICso values in the nanomolar range versus PfNOH2 enzyme and 307 strain of Plasmodium falciparum. Further in vivo studies showed that these two analogues have notable ED50/ED90 against Plasmodium berghei (NS Strain) following oral administration. A series of 6-substituted quinolone esters and pyrrolidine-fused quinolones were also prepared for targeting bc1 complex. They were tested in vitro to explore their structure-activity relationship (SAR). The 6-substituted quinolone ester were synthesised in four steps employing the Gould-Jacobs method. It was noticed that the 3-ester functionality and its steric size are essential for good activity. The 6- substituted quinolone esters possess moderate antimalarial activity with the lead analogue IC50 of 40.4 nM. The 6-substituted quinolone esters were compared head to head with the 7-series of analogues. In an attempt to enhance solubilities, pyrrolidine-fused quinolones were synthesised using Winterfeldt oxidation. Although the compounds were poorly soluble, the potent in vitro result of one of the analogues underlines the potential of the template for further study. Artemisinin and its semi-synthetic derivatives are the most effective drugs in malarial chemotherapy. Despite of their high therapeutic indices, they have poor bioavailability and short half-lives in general. To improve the aqueous solubility and metabolic stability, a series of semi-synthetic C-10 pyrrole Mannich artemisinin derivatives were prepared in 2 steps from dihydroartemisinin. These analogues have demonstrated nanomolar antimalarial activity against the 3D7 strain and Kl strain of Plasmodium falciparum in vitro with high therapeutic indices. Further in vivo studies showed that three of the analogues have excellent ED50/ED90 indicating their overall in vitro and in vivo drug profiles are superior to those of clinically used artemether and artesunate.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available