Indole-based hybrids target both asexual parasites and gametocytes of Plasmodium falciparum and synergize with lumefantrine

Malaria remains a persistent global health challenge, and emerging resistance to artemisinin-based therapy threatens disease control. Here, we report the evaluation of scaffolds selected from three classes of indole hybrids. A library of 24 synthetically designed indoles was screened in vitro against Plasmodium falciparum sexual and asexual forms. The derivatives displayed a wide range of activity, from inactive to potent, with compound ARN53 exhibiting the strongest inhibition (IC₅₀ = 684.8 ± 289.3 nM). Cytotoxicity assays in HEK293T mammalian cells demonstrated the active compounds to be more selective toward the malaria parasite. Remarkably, the potent analogs retained efficacy against the multidrug-resistant Dd2 strain, suggesting a capacity to overcome established resistance mechanisms. Interestingly, ARN53 displayed detectable activity against sexual stages and demonstrated a synergistic effect with lumefantrine, supporting its potential for combination therapy. Overall, these findings expand the chemical diversity of indole scaffolds and highlight ARN53 and its analogs as promising leads for further optimization in antimalarial drug discovery.