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A total of 28 lapachol-related naphthoquinones with four different scaffolds were synthesized and spectroscopically characterized. In vitro antiplasmodial activity was assayed against the chloroquine-resistant Plasmodium falciparum W2 strain by the parasite lactate dehydrogenase (pLDH) method. Cytotoxicity against Hep G2A16 cell was determined by the MTT assay. All compounds disclosed higher in vitro antiplasmodial activity than lapachol. Ortho- and para-naphthoquinones with a furan ring fused to the quinonoid moiety were more potent than 2-hydroxy-3-(1′-alkenyl)-1,4-naphthoquinones, while ortho-furanonaphthoquinones were more cytotoxic. Molecular docking to Plasmodium targets Pfcyt bc1 complex and PfDHOD enzyme showed that five out of the 28 naphthoquinones disclosed favorable binding energies. Furanonaphthoquinones endowed with an aryl moiety linked to the furan ring are highlighted as new in vitro antiplasmodial lead compounds and warrant further investigation.

Objectives To assess the antiplasmodial activity of the ethanol extract of Xylopia sericea leaves, Annonaceae, often associated with antimalarial use and to perform a bioguided isolation of active compounds. Methods Dereplication of ethanol extract by the UPLC‐DAD‐ESI‐MS/MS technique allowed the identification of the major constituents, isolation and identification of alkaloids. The antiplasmodial and cytotoxic activity of the extract, fractions and isolated compounds was evaluated against the chloroquine‐resistant W2 strain Plasmodium falciparum and HepG2 cells, respectively. Key findings Ethanol extract showed high reduction of parasitemia as well as moderate cytotoxicity (86.5 ± 3.0% growth inhibition at 50 μg/ml and CC50 72.1 ± 5.1 μg/ml, respectively). A total of eight flavonoids were identified, and two aporphine alkaloids, anonaine and O‐methylmoschatoline, were isolated. Anonaine disclosed significant antiplasmodial effect and moderate cytotoxicity (IC50 23.2 ± 2.7 μg/ml, CC50 38.3 ± 2.3 μg/ml, SI 1.6) while O‐methylmoschatoline was not active against P. falciparum and showed a low cytotoxicity (33.5 ± 1.9% growth inhibition at 50 μg/ml, CC50 274.4 ± 0.5 μg/ml). Conclusions Characterization of Xylopia sericea leaves ethanol extract by UPLC‐DAD‐ESI‐MS/MS as well as its antiplasmodial activity and the occurrence of anonaine and O‐methylmoschatoline in this Xylopia species are reported by the first time.

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