{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,11]],"date-time":"2026-01-11T16:36:08Z","timestamp":1768149368177,"version":"3.49.0"},"reference-count":46,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T00:00:00Z","timestamp":1749772800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado do Amazonas (FAPEAM)","award":["001\/2017"],"award-info":[{"award-number":["001\/2017"]}]},{"name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado do Amazonas (FAPEAM)","award":["013\/2022"],"award-info":[{"award-number":["013\/2022"]}]},{"name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado do Amazonas (FAPEAM)","award":["001\/2023"],"award-info":[{"award-number":["001\/2023"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Background\/Objectives: Cryptococcosis, caused by Cryptococcus neoformans and Cryptococcus gattii species complexes, remains a significant health concern, particularly among immunocompromised patients. The emergence of antifungal resistance and toxicity of conventional treatment underscore the urgent need for novel therapeutic approaches. Combination therapies represent a promising strategy to enhance efficacy and overcome resistance. This study investigated the antifungal activity of five naphthoquinones against nine isolates of Cryptococcus spp. and assessed their synergistic effects with amphotericin B (AmB). Methods: In this study, five selected naphthoquinones were evaluated for their antifungal activity against Cryptococcus spp. isolates using broth microdilution assays to determine minimum inhibitory concentrations (MICs), according to CLSI guidelines. The potential synergistic effect with AmB was assessed using checkerboard assays, with synergy interpreted based on the fractional inhibitory concentration index (FICI). Cytotoxicity was evaluated in MRC-5 human lung fibroblast cells using the MTT assay. Results: Among the compounds tested, 2-methoxynaphthalene-1,4-dione (2-MNQ) demonstrated antifungal activity, with MIC values ranging from 3.12 to 12.5 \u00b5g\/mL. Checkerboard assays revealed a synergistic interaction between 2-MNQ and AmB, with a fractional inhibitory concentration index (FICI) of 0.27. The combination reduced the MIC of AmB by 4.17-fold. These findings highlight the potential of synthetic naphthoquinones, particularly 2-MNQ, as effective antifungal agents with synergistic properties when combined with AmB. The observed synergy suggests complementary mechanisms, including increased fungal membrane permeability and oxidative stress induction. Conclusions: This study highlights the potential of 2-MNQ and 2,3-DBNQ as antifungal candidates against Cryptococcus spp., with emphasis on the synergistic interaction observed between 2-MNQ and amphotericin B. The findings reinforce the importance of structural modifications in naphthoquinones to enhance antifungal activity and support the need for further preclinical studies investigating combination therapies aimed at improving treatment efficacy in patients with cryptococcosis.<\/jats:p>","DOI":"10.3390\/antibiotics14060602","type":"journal-article","created":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T06:19:28Z","timestamp":1749795568000},"page":"602","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Antifungal Activity of Selected Naphthoquinones and Their Synergistic Combination with Amphotericin B Against Cryptococcus neoformans H99"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9344-1192","authenticated-orcid":false,"given":"Naira Sulany Oliveira de","family":"Sousa","sequence":"first","affiliation":[{"name":"Program in Biodiversity and Biotechnology of the Bionorte Network (PPG-BIONORTE), Amazonas State University (UEA), Manaus 69065-001, AM, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9630-0029","authenticated-orcid":false,"given":"Juan Diego Ribeiro de","family":"Almeida","sequence":"additional","affiliation":[{"name":"Mycology Laboratory, National Institute for Amazonian Research (INPA), Manaus 69067-375, AM, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2446-5216","authenticated-orcid":false,"given":"Linnek Silva da","family":"Rocha","sequence":"additional","affiliation":[{"name":"Mycology Laboratory, National Institute for Amazonian Research (INPA), Manaus 69067-375, AM, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7032-8082","authenticated-orcid":false,"given":"Izabela de Mesquita B\u00e1rcia","family":"Moreira","sequence":"additional","affiliation":[{"name":"Mycology Laboratory, National Institute for Amazonian Research (INPA), Manaus 69067-375, AM, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1591-7025","authenticated-orcid":false,"given":"Fl\u00e1via da Silva","family":"Fernandes","sequence":"additional","affiliation":[{"name":"Mycology Laboratory, National Institute for Amazonian Research (INPA), Manaus 69067-375, AM, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5686-1828","authenticated-orcid":false,"given":"Ani Beatriz Jackisch","family":"Matsuura","sequence":"additional","affiliation":[{"name":"Le\u00f4nidas & Maria Deane Research Center, Oswaldo Cruz Foundation (FIOCRUZ), Manaus 69057-070, AM, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3295-7937","authenticated-orcid":false,"given":"K\u00e1tia Santana","family":"Cruz","sequence":"additional","affiliation":[{"name":"Mycology Laboratory, Dr. Heitor Vieira Dourado Tropical Medicine Foundation (FMT-HVD), Manaus 69040-000, AM, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9367-2812","authenticated-orcid":false,"given":"Emersom Silva","family":"Lima","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Federal University of Amazonas (UFAM), Manaus 69067-005, AM, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2389-4401","authenticated-orcid":false,"given":"\u00c9rica Simpl\u00edcio de","family":"Souza","sequence":"additional","affiliation":[{"name":"Higher School of Technology, Amazonas State University (UEA), Manaus 69050-020, AM, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8967-9528","authenticated-orcid":false,"given":"Hagen","family":"Frickmann","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Virology and Hygiene, University Medicine Rostock, 18057 Rostock, Germany"},{"name":"Department of Microbiology and Hospital Hygiene, Bundeswehr Hospital Hamburg, 22049 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3163-7499","authenticated-orcid":false,"given":"Jo\u00e3o Vicente Braga de","family":"Souza","sequence":"additional","affiliation":[{"name":"Program in Biodiversity and Biotechnology of the Bionorte Network (PPG-BIONORTE), Amazonas State University (UEA), Manaus 69065-001, AM, Brazil"},{"name":"Mycology Laboratory, National Institute for Amazonian Research (INPA), Manaus 69067-375, AM, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1111\/mmi.14565","article-title":"Combatting the evolution of antifungal resistance in Cryptococcus neoformans","volume":"114","author":"Bermas","year":"2020","journal-title":"Mol. 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