This document discusses the design and biological evaluation of heterocyclic quinolones targeting Plasmodium falciparum type II NADH:quinone oxidoreductase (PfNDH2). Key points: 1) There is a need for new antimalarial drugs with novel mechanisms of action to address rising drug resistance. Targeting PfNDH2 is a novel mechanism with potential for curative activity. 2) A screening campaign identified monoaryl quinolones as hits against PfNDH2. Medicinal chemistry optimization incorporated heterocycles like pyridine to reduce drug likeness properties and enhance potency and solubility, yielding lead compound SL-2-25 with low nan