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(Clusiaceae), popularly known as \u201ccebol\u00e3o\u201d or \u201corelha-de-on\u00e7a\u201d, is a Neotropical species recognized as a rich source of bioactive secondary metabolites, particularly prenylated benzophenones. This study investigated the chemical composition and antileishmanial potential of the ethanolic extract (EBCG), dichloromethane fraction (FDCG), and hexane fraction (FHex) obtained from C. grandiflora fruits. Chemical profiling by HPLC-ESI-IT-MS\/MS revealed a metabolome dominated by prenylated benzophenones, terpenes, and flavonols. Biological evaluation included activity against promastigote and axenic amastigote forms of Leishmania (L.) amazonensis, cytotoxicity toward RAW 264.7 macrophages, assessment of cell death phenotypes, nitric oxide (NO) production, and molecular docking against Leishmania infantum trypanothione reductase (TRLi). FDCG and FHex exhibited moderate activity against promastigotes (IC50 = 20.34 and 85.86 \u00b5g mL\u22121, respectively), whereas EBCG was inactive. FHex showed the highest activity against axenic amastigotes (IC50 = 7.0 \u00b5g mL\u22121), while EBCG and FDCG displayed moderate activity (IC50 = 15.92 and 26.43 \u00b5g mL\u22121, respectively). Cell death occurred predominantly through a necrosis-like phenotype in promastigotes and an apoptosis-like phenotype in axenic amastigotes, and all samples significantly reduced NO production. Molecular docking indicated that several putatively annotated metabolites from C. grandiflora can be favorably accommodated within the TS2 substrate-binding cavity of Leishmania infantum trypanothione reductase (TRLi). Garcinielliptone I and Guttiferone E exhibited the most favorable predicted binding affinities, whereas xanthocymol displayed an interaction pattern involving the catalytic residues Cys52 and Cys57. These findings highlight selected putatively annotated metabolites as promising candidates for future biochemical investigation. Overall, these findings highlight C. grandiflora fruits as a promising, previously underexplored source of prenylated benzophenones with antileishmanial activity and the ability to reduce nitric oxide production in LPS-stimulated RAW 264.7 macrophages.<\/jats:p>","DOI":"10.3390\/molecules31162859","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T10:04:36Z","timestamp":1786961076000},"page":"2859","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chemical Annotation and Biological Evaluation of Prenylated Benzophenone-Rich Fractions from Clusia grandiflora Fruits: Integrated In Vitro and In Silico Analyses of Antileishmanial Activity, Nitric Oxide Modulation, and Stage-Dependent Cell Death Phenotypes"],"prefix":"10.3390","volume":"31","author":[{"given":"Amanda","family":"de Jesus Alves Miranda","sequence":"first","affiliation":[{"name":"Natural Products Chemistry Laboratory, Department of Chemistry, Federal University of Maranh\u00e3o, S\u00e3o Lu\u00eds 65080-805, MA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline Martins","family":"de Jesus","sequence":"additional","affiliation":[{"name":"Parasitology and Immunology Laboratory, Center for Biological and Health Sciences, Federal University of Maranh\u00e3o, S\u00e3o Lu\u00eds 65080-805, MA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2906-0588","authenticated-orcid":false,"given":"Kassandra G\u00f3mez","family":"Valenzuela","sequence":"additional","affiliation":[{"name":"Natural Resources Research Laboratory, University of Sonora, Hermosillo 83000, Sonora, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5043-0782","authenticated-orcid":false,"given":"Jos\u00e9 Alberto P\u00e9rez","family":"Burgos","sequence":"additional","affiliation":[{"name":"Natural Resources Research Laboratory, University of Sonora, Hermosillo 83000, Sonora, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2411-5123","authenticated-orcid":false,"given":"Samuel","family":"dos Santos Soares Buna","sequence":"additional","affiliation":[{"name":"Natural Products Chemistry Laboratory, Department of Chemistry, Federal University of Maranh\u00e3o, S\u00e3o Lu\u00eds 65080-805, MA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00edvia Maria Martins","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Natural Products Chemistry Laboratory, Department of Chemistry, Federal University of Maranh\u00e3o, S\u00e3o Lu\u00eds 65080-805, MA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas Cardoso","family":"Marinho","sequence":"additional","affiliation":[{"name":"Laboratory of the Angiosperm Systematics and Taxonomy Research Group, Department of Biology, Federal University of Maranh\u00e3o, S\u00e3o Lu\u00eds 65080-805, MA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"de Sousa Lima Neto","sequence":"additional","affiliation":[{"name":"Laboratory for Advanced Studies in Phytomedicines, Department of Biology, Federal University of Maranh\u00e3o, S\u00e3o Lu\u00eds 65080-805, MA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8988-5532","authenticated-orcid":false,"given":"Marcelo Jos\u00e9 Dias","family":"Silva","sequence":"additional","affiliation":[{"name":"Graduate Program in Pharmaceutical Care, Department of Food and Drugs, Federal University of Alfenas, Alfenas 37130-001, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5267-9500","authenticated-orcid":false,"given":"Alberto Jorge Oliveira","family":"Lopes","sequence":"additional","affiliation":[{"name":"Natural 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