Compounds 5e and 5f combine the ethylphenyl(4-methoxyphenyl) ether scaffold of 4i with the benzyl and methyl N10 modifications from 2c or 1b, respectively. Both compounds are nanomolar inhibitors of both PTR1 variants. The parent compounds, 2c and 1b, inhibit the parasite DHFR variants at micromolar to submicromolar levels, while 4i is inactive against all variants of DHFR. The combination with a favorable N10 substitution is able to restore medium micromolar anti-DHFR activity for the altered scaffold of parent 4i in the parasite enzymes in 5e and 5f. Thus, combined N10 and tail modifications allowed for the species-specific optimization of the target inhibition profile.