The modulated on-target/off-target activities and selectivities of the above compounds showed that specific combinations of the N10 and tail modifications allow a fine-tuning of the target inhibition profile for enzymes of specific parasite species. Furthermore, the strategy employed here of combining property prediction correlation with multitarget-based compound design was found to be a useful approach to discovering antiparasitic agents, even when the antiparasitic data are available only as a percentage of inhibition determined at a single compound concentration. We also note that the presence of high folate concentrations in the HMI-9 medium used in the parasite assays may have resulted in underestimated anti-parasitic activity due to competition between folic acid and folate-analogue inhibitors of DHFR.