(2015-05) Nethavhani, Sedzani A.; van Ree, T.; Ramaite, I. D. I.
The overall objective of this project was to design and synthesize cysteinyl protease inhibitors that are envisaged to have antimalarial activity. Several synthesis routes leading to the rigid heterocyclic 2-pyridone scaffold were explored. The syntheses of the 2-pyridones involved constructing and investigating derivatives with hydrophilic and hydrophobic moieties, using a methodology that seems to have a wide scope. Intermediates as well as the target pyridones were docked into the falcipain-2 active site and tested against chloroquine sensitive and resistant Plasmodium falciparum strains; three 3-cyano-2-pyridones showed promising results. Using this collection of synthesis methodologies, a wide variety of di- and tripeptides based on a substituted 2-pyridone scaffold in the P2 position, have become accessible.