Novel 3,3'-disubstituted-5,5'-bi(1,2,4-triazine) compounds with potent <i>in vitro</i> activity against <i>Plasmodium falciparum</i> parasites were recently discovered. To improve the pharmacokinetic properties of the triazine derivatives, a new structure-activity relationship (SAR) investigation was initiated with a focus on enhancing the metabolic stability of lead compounds. These efforts led to the identification of second-generation highly potent antimalarial bis-triazines, exemplified by triazine <b>23</b>, which exhibited significantly improved <i>in vitro</i> metabolic stability (8 and 42 μL/min/mg protein in human and mouse liver microsomes). The disubstituted triazine dimer <b>23</b> was also observed to suppress parasitemia in the Peters 4-day test with a mean ED<sub>50</sub> value of 1.85 mg/kg/day and exhibited a fast-killing profile, revealing a new class of orally available antimalarial compounds of considerable interest.