This thesis describes efforts to identify novel derivatives with improved physicochemical and solubility properties whilst maintaining, if not improving the antimalarial potencies and safety margins shown by the parent 4(1H)-pyridones.
The synthesis of a phosphate prodrug has validated the strategy as a successful approach to overcoming limited oral bioavailability and poor solubility of classical 4(1H)-pyridones. Furthermore, this prodrug was associated with improved linearity in dose-escalation studies, allowing the progression of the family to further development stages.
In addition, a series of cyclic 4(1H)-pyridones has been studied and validated, constituting a promising family of antimalarial compounds that maintain excellent in vitro activity and in vivo efficacy in both P. yoelii model and P. falciparum humanized mouse model. Pharmacological and molecular modeling data presented in this thesis suggest a slightly different active site binding pose is being adopted by this novel family of tricyclic 4(1H)-pyridone derivatives, offering the opportunity to overcome safety issues found in the classical 4(1H)-pyridones.
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