Simarouba berteroana: A Promising Source of Bioactive Compounds with Potential to Enhance Artesunate Activity Against Plasmodium falciparum

Malaria remains a major global health challenge, exacerbated by the emergence of antimalarial drug resistance. Natural products are valuable sources of structurally diverse bioactive compounds, including quassinoids from the Simaroubaceae family, which have shown antiplasmodial activity. In this context, species of the genus Simarouba are promising candidates for investigating new sources of antimalarial compounds. In this context, hydroethanolic extracts of Simarouba berteroana, collected during different seasons, were investigated for their in vitro activity against chloroquine-sensitive (3D7) and chloroquine-resistant (W2) strains of Plasmodium falciparum. Cytotoxicity was assessed using the MTT assay in HUVEC and HepG2 cells exposed to the extracts (1.46–1500 μg/mL) for 48 h. Sb1 and Sb2 showed IC₅₀ values of 37.36 ± 4.57 and 43.17
± 2.32 μg/mL in HUVEC cells, respectively, and 102.80 ± 2.55 and 108.70 ± 0.99 μg/mL in HepG2 cells, respectively. Antiplasmodial activity was evaluated against chloroquine-sensitive (3D7) and chloroquine-resistant (W2) strains of Plasmodium falciparum using the SYBR Gold fluorescence assay. Synchronized ring-stage parasites (1% parasitemia and 2% hematocrit) were exposed to the extracts (0.23–60.00 μg/mL) for 48 h. Sb1 and Sb2 showed IC₅₀ values of 3.06 and 3.13 μg/mL, respectively, against 3D7, and 1.49 and 1.32 μg/mL, respectively, against W2. The activity observed against both strains, including the chloroquine-resistant W2 strain, supports further investigation of these extracts as potential sources of antiplasmodial bioactive compounds. To investigate whether the extracts could enhance artesunate activity, combination assays were performed against the 3D7 strain using fixed extract concentrations (0.47 and 0.94 μg/mL). Artesunate IC₅₀ values were determined in the absence and presence of each extract using the SYBR Gold fluorescence assay after 48 h. Artesunate alone showed an IC₅₀ of 2.98 nM, which decreased to 2.41 and 1.12 nM in the presence of Sb1 at 0.47 and 0.94 μg/mL, respectively. With Sb2, the corresponding IC₅₀ values were 2.93 and 1.65 nM, respectively. These findings indicate that both extracts reduced the concentration of artesunate required to inhibit parasite growth by 50%, with the magnitude of this effect varying according to the extract and concentration tested. The antiplasmodial activity of Simarouba berteroana extracts against both chloroquine-sensitive and chloroquine-resistant P. falciparum strains highlights their potential as sources of antimalarial bioactive compounds. Moreover, the reduction in artesunate IC₅₀ in the presence of both extracts supports further investigation of their potential to enhance antimalarial drug activity. Acknowledgments: We acknowledge the financial support provided by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and the Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG).