A phenotypic high-throughput screen allowed discovery of quinazolinone-2-carboxamide derivatives as a novel antimalarial scaffold. Structure-activity relationship studies led to identification of a potent inhibitor <b>19f</b>, 95-fold more potent than the original hit compound, active against laboratory-resistant strains of malaria. Profiling of <b>19f</b> suggested a fast <i>in vitro</i> killing profile. <i>In vivo</i> activity in a murine model of human malaria in a dose-dependent manner constitutes a concomitant benefit.