Exploring a Tetrahydroquinoline Antimalarial Hit from the Medicines for Malaria Pathogen Box and Identification of its Mode of Resistance as PfeEF2

New antimalarial treatments with novel mechanism of action are needed to tackle Plasmodium falciparum infections that are resistant to first‐line therapeutics. Here we report the exploration of MMV692140 (2) from the Pathogen Box, a collection of 400 compounds that was made available by Medicines for Malaria Venture (MMV) in 2015. Compound 2 was profiled in in vitro models of malaria and was found to be active against multiple life‐cycle stages of Plasmodium parasites. The mode of resistance, and putatively its mode of action, was identified as Plasmodium falciparum translation elongation factor 2 (PfeEF2), which is responsible for the GTP‐dependent translocation of the ribosome along mRNA. The compound maintains activity against a series of drug‐resistant parasite strains. The structural motif of the tetrahydroquinoline (2) was explored in a chemistry program with its structure‐activity relationships examined, resulting in the identification of an analog with 30‐fold improvement of antimalarial asexual blood stage potency.