Design and synthesis of potential malaria cysteinyl protease inhibitors

Abstract

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.