Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.679789
Title: Design, synthesis and antimalarial evaluation of novel azafluorenone analogues
Author: Huang, Xiangchen
ISNI:       0000 0004 5372 1119
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2016
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Abstract:
With the rapid spread of drug resistance to chloroquine, the development of effective, safe, and affordable antimalrial drugs has become one of the most pressing health priorities worldwide. Two azafluorenone alkaloids isolated from Mitrephora diversifolia have been proved to possess antimalarial activity against chloroquine-resistant Plasmodium falciparum. To explore the structure-activity relationship of the azafluorenone family, twenty four analogues with various structural modifications have been prepared via a concise synthetic route utilising Suzuki cross-doupling reactions and intramolecular Friedel-Crafts acylations as the key steps. A series of hybrid molecules conjugating the azafluorenone core and the amino side chains present in 4-aminoquinoline antimalarial agents have also been synthesised. Fourteen of the azafluorenones have been evaluated for antiplasmodial activity by by [3H]hypoxanthine-incorporation assay. Eight azafluorenones display activity against chloroquine-sensitive Plasmodium falciparum 3D7, and nine azafluorenones are active against chloroquine-resistant Plasmodium falciparum K1. The hybrid molecules prepared possess a much higher antimalarial potency than the other azafluorenones, which can be attributed to the additional interaction between the amino side chains and the target site. An in vitro β-haematin inhibition assay has been conducted to probe the mode of action of the azafluorenones. However, only two azafluorenones show mild inhibitory activity against β-haematin formation. Four distinct sytnthetic routes have been investigated for the total synthesis of the parent antimalarial natural product. However, each of these fails to afford the desired alkaloid. An efficient one-pot method for the synthesis of pyrido[3,2-c]coumarins has been developed. Twenty seven pyrido[3,2-c]coumarin derivatives have been prepared in moderate to excellent yields under the optimised thermal conditions, confirming the versality of this protocol. Nine pyrido[3,2-c]coumarin analogues have been synthesised in moderate to go good yields under microwave-assisted conditions. The mechanism of this one-pot reaction has been explored. The good yields, concise synthetic route. wide availability pf subtrates and milder reaction conditions render this one-pot protocol superior to other commonly used methods and make it a feasible approach to the synthesis of pyrido[3,2-c]coumarins in gram quantities.
Supervisor: Mountford, David Mark ; Barlow, David John Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.679789  DOI: Not available
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