As a first modification to the PABA moiety, in 3a, we replaced the PABA phenyl group with benzyl (Figure ). The additional hydrophobic spacer can interact with hydrophobic target residues, while resulting in a shifted position of the hydrophilic linker amide. The positioning of hydrophobic and hydrophilic residues surrounding the PABA moiety and the amide linker in the human off-target is different from the parasite targets PTR1 and DHFR, which can be exploited to improve selectivity. For the same reason, the amide linker position was also shifted in 3b by substituting the PABA moiety with meta-aminobenzoic acid. A second key feature of the targets vs. off-targets that was used to inform the design of the PABA-series relates to the compound tail: Tail regions are solvent-exposed in PTR1 and thus have poorly defined interactions (Figure ). In contrast, in DHFR, the tail region is enclosed, and strong interactions occur with the hDHFR off-target. We therefore shortened the tail region to achieve full enclosure in the PTR1 binding pocket by replacing PABA by naphthalene (3c) or benzene moieties (non-substituted, 3d; or substituted with -CF3, 3e). Docking results