Indole Peptidomimetics Show Potent and Selective Activity against Drug-Resistant <i>Plasmodium falciparum</i>

Malaria remains a global health challenge exacerbated by emerging drug-resistant Plasmodium falciparum strains. Here, we report the design, synthesis, and biological evaluation of indole-based peptidomimetics against P. falciparum sensitive and multidrug-resistant strains. Structure–activity relationship analysis indicated that aromatic and halogen substituents, as well as modifications at the indole nitrogen and amide linkage, strongly influence potency and selectivity. LSPN954 (4i) and LSPN959 (4k) emerged as front-runner compounds, displaying low micromolar potency against the sensitive strain (IC503D7 = 1.7 and 1.0 μM, respectively), low cytotoxic effects on HepG2 and HEK293 human cells (CC50 ≥ 100 μM), and high selectivity indices (SI = 59 and 95, respectively). In addition, these compounds demonstrated a slow-acting profile, additive effects with artesunate, and retained efficacy against multiple resistant strains (Dd2, K1, Dd2R_DSM265, and 3D7R_MMV848), exhibiting no cross-resistance. These findings highlight indole peptidomimetics as promising scaffolds for antimalarial drug development, providing a foundation for further optimization toward potent, selective agents capable of overcoming current resistance mechanisms.