Methods to identify the bioactive diversity within natural product extracts (NPEs) continue to evolve. NPEs constitute complex mixtures of chemical substances varying in structure, composition and abundance. NPEs can therefore be challenging to evaluate efficiently with high throughput screening approaches designed to test pure substances. Here we facilitate the rapid identification and prioritization of anti-malarial NPEs using a pharmacologically-driven, quantitative high throughput screening (qHTS) paradigm. In qHTS each NPE is tested across a concentration range from which sigmoidal response, efficacy and apparent EC50s can be used to rank order NPEs for subsequent organism re-culture, extraction and fractionation. Using an NPE library derived from diverse marine microorganisms we observed potent antimalarial activity from two Streptomyces sp. extracts identified from thousands tested using qHTS. Seven compounds were isolated from two phylogenetically related Streptomyces species; Streptomyces ballenaensis collected from Costa Rica and Streptomyces bangulaensis collected from Papua New Guinea. Among them we identified actinoramides A and B belonging to the unusually elaborated non-proteinogenic amino acid-containing tetrapeptide series of natural products. In addition, we characterized a series of new compounds, including an artifact 25-epi-actinoramide A, and actinoramides D, E, F which are closely related biosynthetic congeners of the previously reported metabolites.