Pocket size and interaction pattern differences between LmDHFR and other DHFR variants, as also discussed for the PABA series, also affect the Tail-modified compounds: For instance, 4d is more active against both TbDHFR and hDHFR than 1c (IC50 TbDHFR 1 vs. 21 μM, hDHFR 6 vs. 51 μM), while both compounds show similar activity for LmDHFR.