We tested Pfmrk against several naphthalene and isoquinoline sulfonamides previously reported as protein kinase A (PKA) inhibitors. Pfmrk is a Cyclin Dependent protein Kinase (CDK) from Plasmodium falciparum, the causative parasite of the most lethal form of malaria. We find that the isoquinoline sulfonamides are potent inhibitors of Pfmrk and that substitution on the 5 position of the isoquinoline ring greatly influences the degree of potency. Molecular modeling studies suggest that the nitrogen atom in the isoquinoline ring plays a key role in ligand-receptor interactions. Structural analysis suggests that even subtle differences in amino acid composition within the active sites are responsible for conferring specificity of these inhibitors for Pfmrk over PKA.