Introduction of Scaffold Nitrogen Atoms Renders Inhibitors of the Malarial l‑Lactate Transporter, PfFNT, Effective against the Gly107Ser Resistance Mutation

The spreading of malaria parasites, Plasmodium falciparum, with resistance to all known drugs calls for novel classes of inhibitors with new modes of action. Recently, we discovered and validated the plasmodial l-lactate transporter, PfFNT, as a novel antimalarial drug target. However, treatment of parasites with a screening hit from the malaria box compound collection, MMV007839, gave rise to a PfFNT Gly107Ser resistance mutation decreasing inhibitor affinity by 2 orders of magnitude. Here, we show that newly introduced nitrogen atoms into the inhibitor scaffold can act as hydrogen bond acceptor sites to the serine hydroxyl. The gain in affinity led to almost equal inhibition of wildtype PfFNT and the Gly107Ser mutation. The most potent inhibitor of this work, BH267.meta, killed cultured P. falciparum parasites with nanomolar efficacy and did not give rise to new resistance formation in vitro. Its deduced pharmacokinetic properties appear suitable for further drug development.