Docking studies suggested that even substituents of the size of benzyl, as in 2c, can be accommodated in the PTR1 and DHFR pockets (Figure ). Furthermore, such bulky substituents may improve selectivity for the on-targets: The hDHFR pocket has a lower volume compared to the parasite DHFR pockets (pocket volume TbDHFR 353 Å 3 , LmDHFR 384 Å and hDHFR 347 Å 3 ).