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.