Design, Synthesis and Biological Evaluation of Novel 4(1H)-Pyridones as Antimalarial Inhibitors of Plasmodium falciparum Cytochrome bc1
Author
Puente Felipe, MargaritaAdvisor
Manzano Chinchón, PilarEntity
UAM. Departamento de Química OrgánicaDate
2018-10-26Subjects
Paludismo - Tesis doctorales; Inhibidores de fosfodiesterasas - Tesis doctorales; QuímicaNote
Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Química Orgánica. Fecha de lectura: 26-10-2018Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
Malaria remains one of the most widespread infectious diseases of our time.
Resistance to all current chemotherapeutics used in the treatment of this illness has
been observed. Therefore, there is an urgent requirement for the development of novel
agents to combat this disease, particularly against those strains which have developed
resistance to previously used therapies.
The mitochondrial respiratory chain of P. falciparum makes an attractive target for
chemotherapy, being both chemically and clinically validated by atovaquone.
Furthermore, the parasitic respiratory chain differs from the analogous mammalian
system, suggesting that parasite specific agents should be achievable. 4(1H)-Pyridones
have been developed at GlaxoSmithKline as selective inhibitors of Plasmodium
mitochondrial function by blocking the electron transport chain at the cytochrome bc1
level. However, the most potent 4-pyridones are lipophilic molecules with poor
solubility in aqueous media and low oral bioavailability.
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 doseescalation
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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Google Scholar:Puente Felipe, Margarita
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