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These facts have driven research toward the discovery of new compounds for the treatment of cryptococcosis. In this study, we investigated the therapeutic potential of two complexes, [Cu(phendione)3](ClO4)2\u00b74H2O (Cu-phendione) and [Ag(phendione)2]ClO4 (Ag-phendione), against drug-resistant clinical isolates of C. gattii and C. neoformans. Both complexes demonstrated anti-Cryptococcus activity, with Cu-phendione exhibiting minimum inhibitory concentration (MIC) values of 6.25 \u03bcM for C. gattii and 3.125 \u03bcM for C. neoformans, while Ag-phendione showed an MIC of 1.56 \u03bcM for both Cryptococcus species. Notably, both Cu-phendione and Ag-phendione complexes exhibited enhanced antifungal activity against reference strains of C. neoformans and C. gattii. In silico analysis identified both complexes as highly promising, exhibiting good oral bioavailability, high gastrointestinal absorption, and moderate skin permeability. Moreover, neither complex demonstrated toxicity toward sheep erythrocytes at concentrations up to 62.5 \u03bcM, with a selectivity index (SI) exceeding 10 for Cu-phendione and 40 for Ag-phendione. In vivo testing using the Galleria mellonella model demonstrated that both complexes were non-toxic, with 100% larval survival at concentrations up to 1000 \u03bcM and SI exceeding 160 following a single administration. Interestingly, larvae exposed to Cu-phendione at concentrations of 15.6\u201331.25 \u03bcM exhibited a significant increase in the density of hemocytes, the immune cells responsible for defense in invertebrates. Furthermore, multiple treatments with 62.5 \u03bcM of complexes caused either no larval mortality, hemocyte alterations, or changes in silk production or coloration, indicating a lack of toxicity. These findings suggest that Cu-phendione and Ag-phendione may serve as promising antifungal alternatives against Cryptococcus, with minimal host toxicity.<\/jats:p>","DOI":"10.3390\/jof11060436","type":"journal-article","created":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T11:08:31Z","timestamp":1749208111000},"page":"436","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Toxicity Assessment and Antifungal Potential of Copper(II) and Silver(I) Complexes with 1,10-Phenanthroline-5,6-dione Against Drug-Resistant Clinical Isolates of Cryptococcus gattii and Cryptococcus neoformans"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-5036-3837","authenticated-orcid":false,"given":"Lucas","family":"Giovanini","sequence":"first","affiliation":[{"name":"Laborat\u00f3rio de Estudos Avan\u00e7ados de Microrganismos Emergentes e Resistentes (LEAMER), Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de G\u00f3es (IMPG), Centro de Ci\u00eancias da Sa\u00fade (CCS), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-901, RJ, Brazil"},{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Microbiologia (PPG-Micro), Instituto de Microbiologia Paulo de G\u00f3es (IMPG), Centro de Ci\u00eancias da Sa\u00fade (CCS), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-901, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Lucia","family":"Casemiro","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Estudos Avan\u00e7ados de Microrganismos Emergentes e Resistentes (LEAMER), Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de G\u00f3es (IMPG), Centro de Ci\u00eancias da Sa\u00fade (CCS), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-901, RJ, Brazil"},{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Microbiologia (PPG-Micro), Instituto de Microbiologia Paulo de G\u00f3es (IMPG), Centro de Ci\u00eancias da Sa\u00fade (CCS), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-901, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larissa S.","family":"Corr\u00eaa","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Estudos Avan\u00e7ados de Microrganismos Emergentes e Resistentes (LEAMER), Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de G\u00f3es (IMPG), Centro de Ci\u00eancias da Sa\u00fade (CCS), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-901, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matheus","family":"Mendes","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Estudos Avan\u00e7ados de Microrganismos Emergentes e Resistentes (LEAMER), Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de G\u00f3es (IMPG), Centro de Ci\u00eancias da Sa\u00fade (CCS), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-901, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5820-2241","authenticated-orcid":false,"given":"Tha\u00eds P.","family":"Mello","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Estudos Avan\u00e7ados de Microrganismos Emergentes e Resistentes (LEAMER), Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de G\u00f3es (IMPG), Centro de Ci\u00eancias da Sa\u00fade (CCS), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-901, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucieri O. 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Kildare, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9752-8148","authenticated-orcid":false,"given":"Marta H.","family":"Branquinha","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Estudos Avan\u00e7ados de Microrganismos Emergentes e Resistentes (LEAMER), Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de G\u00f3es (IMPG), Centro de Ci\u00eancias da Sa\u00fade (CCS), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-901, RJ, Brazil"},{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Microbiologia (PPG-Micro), Instituto de Microbiologia Paulo de G\u00f3es (IMPG), Centro de Ci\u00eancias da Sa\u00fade (CCS), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-901, RJ, Brazil"},{"name":"Rede Micologia RJ, Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro (FAPERJ), Rio de Janeiro 21941-901, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0821-8592","authenticated-orcid":false,"given":"Andr\u00e9 L. 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Dis."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Williams, S.L., Toda, M., Chiller, T., Brunkard, J.M., and Litvintseva, A.P. (2024). Effects of climate change on fungal infections. PLoS Pathog., 20.","DOI":"10.1371\/journal.ppat.1012219"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s40249-023-01073-4","article-title":"Cryptococcus neoformans, a global threat to human health","volume":"12","author":"Zhao","year":"2023","journal-title":"Infect. Dis. Poverty"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Gbadamosi, H., Afriyie-Mensah, J.S., Ansah, E.N., Dadzie, S.K., and Puplampu, P. (2024). A rare case of disseminated pulmonary cryptococcosis in an immunocompetent patient. BMC Pulm. Med., 24.","DOI":"10.1186\/s12890-024-03318-w"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Lee, Y.M., Liu, Y.M., and Chen, T.C. (2024). Disseminated Cryptococcus neoformans infection involving multiple bones and lung in an immunocompetent patient: A case report. BMC Infect. Dis., 24.","DOI":"10.1186\/s12879-024-09264-6"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e376","DOI":"10.1097\/WNO.0000000000001935","article-title":"Cryptococcal meningitis with immune-reconstitution inflammatory syndrome causing papilledema and visual field defects in an immunocompetent patient","volume":"44","author":"Maccora","year":"2024","journal-title":"J. Neuroophthalmol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.2169\/internalmedicine.1944-23","article-title":"Clinical characteristics of patients with cryptococcal meningitis in Hokkaido: A case series","volume":"63","author":"Tarisawa","year":"2024","journal-title":"Intern. Med."},{"key":"ref_8","unstructured":"World Health Organization (WHO) (2022). 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