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Safety and efficacy concerns with currently used drugs accentuate the need for new chemotherapeutic options against severe malaria. Here we describe a medicinal chemistry program starting from amicarbalide that led to two compounds with optimized pharmacological and antiparasitic properties. SC81458 and the clinical development candidate, SC83288, are fast-acting compounds that can cure a <jats:italic>P. falciparum<\/jats:italic> infection in a humanized NOD\/SCID mouse model system. Detailed preclinical pharmacokinetic and toxicological studies reveal no observable drawbacks. Ultra-deep sequencing of resistant parasites identifies the sarco\/endoplasmic reticulum Ca<jats:sup>2+<\/jats:sup> transporting PfATP6 as a putative determinant of resistance to SC81458 and SC83288. 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