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Indole Peptidomimetics Show Potent and Selective Activity against Drug-Resistant Plasmodium falciparum
Marcelo Augusto Pereira Januário1, Talita Alvarenga Valdes2, Sarah El Chamy Maluf2
1Centre of Excellence for Research in Sustainable Chemistry, Department of Chemistry, Federal University of São Carlos, São Carlos 13565-905, Brazil.
Abstract:
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 (IC50 3D7 = 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.
Insights
New indole-based drugs show promise against malaria, even drug-resistant strains. These compounds are potent, selective, and effective against multiple resistant Plasmodium falciparum strains, offering hope for malaria treatment.
Area of Science:
- Medicinal Chemistry
- Parasitology
- Drug Discovery
Background:
- Malaria remains a significant global health burden.
- Emerging drug resistance in Plasmodium falciparum complicates treatment strategies.
Purpose of the Study:
- To design, synthesize, and evaluate novel indole-based peptidomimetics as potential antimalarial agents.
- To identify compounds effective against both sensitive and multidrug-resistant malaria strains.
Main Methods:
- Structure-activity relationship (SAR) studies were conducted on synthesized indole derivatives.
- Biological evaluation included in vitro testing against sensitive and resistant Plasmodium falciparum strains.
- Cytotoxicity assays were performed on human cell lines (HepG2, HEK293) to assess selectivity.
Main Results:
- Compounds LSPN954 (4i) and LSPN959 (4k) exhibited low micromolar potency against the sensitive 3D7 strain (IC50 = 1.7 and 1.0 μM).
- These compounds demonstrated low cytotoxicity (CC50 ≥ 100 μM) and high selectivity indices (SI = 59 and 95).
- LSPN954 and LSPN959 retained efficacy against multiple resistant strains (Dd2, K1, Dd2R_DSM265, 3D7R_MMV848) with no cross-resistance.
Conclusions:
- Indole-based peptidomimetics represent a promising scaffold for developing new antimalarial drugs.
- The identified front-runner compounds offer a foundation for further optimization to combat drug-resistant malaria.
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