Antimalarial Activity of Endophytic Fungi from Breadfruit (Artocarpus altilis) Leaves: Heme Polymerization Inhibition, Metabolite Profiling, and Molecular Docking Analysis

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Malaria remains a major global health challenge and requiring the continuous discovery of new and effective antimalarial agent to combat drug resistance. The production of natural antimalaria drugs often requires large amount of plant biomass that raising seriuos concern about plany consevation and resource sustainability. Endophytic fungi, which biosynthesize the same metabolites as their host plant, represent an alternative source of bioactive compounds with therapeutic potential, including antimalarial activity. This study aimed to isolate and characterize endophytic fungi from breadfruit (Artocarpus altilis) leaves, evaluate their antimalarial activity, identify their major metabolites, and analyze their molecular interactions with Plasmodium falciparum heme detoxification proteins. Endophytic fungi were isolated using the surface sterilization method and cultured on PDA medium, and then on rice medium. The ethyl acetate extracts of the selected isolates were evaluated for antimalarial activity against P. falciparum using the heme polymerization inhibition assay. The most active extract derived from JDSUM4 isolate (IC50 = 0.46 ± 0.15 µg/mL), was molecularly identified as Aspergillus flavus. The extract was subsequently analyzed using LC-MS/MS, which revealed ten major secondary metabolites. These compounds were selected based on Lipinski’s Rule of Five and subsequently subjected to molecular docking against heme peroxidase and histidine-rich protein 2 (HRP-2). Docking analysis showed that all compounds possessed favorable binding affinities, ranging from −4.0 to −6.3 kcal/mol for heme peroxidase and −4.2 to −8.1 kcal/mol for HRP-2. Among them, emodin, fluvastatin, and mycophenolic acid exhibited the strong affinity toward both targets, comparable to artemisinin as a positive control. Collectively, these findings indicate that metabolites from A. altilis leaf endophytic fungi, particularly those produced by isolate JDSUM4, hold promise as novel sources of natural antimalarial compounds targeting multiple heme detoxification pathways. HIGHLIGHTS Endophytic fungi from Artocarpus altilis were explored as a sustainable alternative source of antimalarial compounds. Seven isolates were screened, with Aspergillus flavus JDSUM4 showing the most potent activity (IC50 = 0.46 ± 0.15 µg/mL). LC-MS/MS profiling revealed diverse metabolites, including anthraquinones, diterpenoids, and fatty acids with potential synergistic effects. Molecular docking analysis identified emodin, fluvastatine, and mycophenolic acid as the secondary metabolites that show strongest interaction to heme detoxification related protein. This study demonstrates a eco-friendly approach for discovering antimalarial agent from fungal endophytes. GRAPHICAL ABSTRACT

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