The tetrahydro-β-carboline scaffold has proven fertile ground for the discovery of antimalarial agents (e.g., MMV008138 (<b>1</b>) and cipargamin (<b>2</b>)). Similarity searching of a publicly disclosed collection of antimalarial hits for molecules resembling <b>1</b> drew our attention to N2-acyl tetrahydro-β-carboline GNF-Pf-5009 ((±)-<b>3b</b>). Compound purchase, "analog by catalog", and independent synthesis of hits indicated the benzofuran-2-yl amide portion was required for <i>in vitro</i> efficacy against <i>P. falciparum</i>. Preparation of pure enantiomers demonstrated the pharmacological superiority of (<i>R</i>)-<b>3b</b>. Synthesis and evaluation of D- and F-ring substitution variants and benzofuran isosteres indicated a clear structure-activity relationship. Ultimately (<i>R</i>)-<b>3b</b> was tested in <i>Plasmodium berghei</i>-infected mice; unfavorable physicochemical properties may be responsible for the lack of oral efficacy.