Hameed P., ShahulSolapure, SureshPatil, VikasHenrich, Philipp P.Magistrado, PamelaBharath, SowmyaMurugan, KannanViswanath, PavithraPuttur, JayashreeSrivastava, AbhishekBellale, EknathPanduga, VijenderShanbag, GajananAwasthy, DishaLandge, SudhirMorayya, SapnaKoushik, KrishnaSaralaya, RamanathaRaichurkar, AnandkumarRautela, NikhilRoy Choudhury, NilanjanaAmbady, AnishaNandishaiah, RadhaReddy, JitendarPrabhakar, K. R.Menasinakai, SreenivasaiahRudrapatna, SureshChatterji, MonalisaJiménez-Díaz, María BelénMartínez, María SantosSanz, Laura MaríaCoburn-Flynn, OliviaFidock, David A.Lukens, AmandaWirth, DyannBandodkar, BalachandraMukherjee, KakoliMcLaughlin, Robert E.Waterson, DavidRosenbrier-Ribeiro, LynHickling, KevinBalasubramanian, V.Warner, PeterHosagrahara, VinayakDudley, AdamIyer, Pravin S.Narayanan, ShridharKavanagh, StefanSambandamurthy, Vasan K.2015-05-042015Hameed P., S., S. Solapure, V. Patil, P. P. Henrich, P. A. Magistrado, S. Bharath, K. Murugan, et al. 2015. “Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate.” Nature Communications 6 (1): 6715. doi:10.1038/ncomms7715. http://dx.doi.org/10.1038/ncomms7715.2041-1723http://nrs.harvard.edu/urn-3:HUL.InstRepos:15034849The widespread emergence of Plasmodium falciparum (Pf) strains resistant to frontline agents has fuelled the search for fast-acting agents with novel mechanism of action. Here, we report the discovery and optimization of novel antimalarial compounds, the triaminopyrimidines (TAPs), which emerged from a phenotypic screen against the blood stages of Pf. The clinical candidate (compound 12) is efficacious in a mouse model of Pf malaria with an ED99 <30 mg kg−1 and displays good in vivo safety margins in guinea pigs and rats. With a predicted half-life of 36 h in humans, a single dose of 260 mg might be sufficient to maintain therapeutic blood concentration for 4–5 days. Whole-genome sequencing of resistant mutants implicates the vacuolar ATP synthase as a genetic determinant of resistance to TAPs. Our studies highlight the potential of TAPs for single-dose treatment of Pf malaria in combination with other agents in clinical development.en-USJournal Article2015-05-0410.1038/ncomms7715