{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:36:28Z","timestamp":1760060188602,"version":"build-2065373602"},"reference-count":24,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T00:00:00Z","timestamp":1754438400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Messina (Italy)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Candidiasis arises from the proliferation of Candida species in the human body, especially in individuals with compromised immune systems. Efficient therapeutic management of candidiasis is often hampered by the limited availability of potent antifungal drugs and the emergence of drug-resistant strains. We have previously identified the N-[(4-sulfamoylphenyl)methyl][1,1\u2032-biphenyl]-4-carboxamide to have fungistatic and fungicidal properties, likely due to the hydrophobic biphenyl\u2013chemical features affecting the structural organization of Candida spp. cell membrane. Here, we designed and synthesized a novel series of twelve 5-arylfuran-2-carboxamide derivatives bearing a new hydrophobic tail as bioisosteric replacement of the diphenyl fragment. Its antifungal effectiveness against C. albicans, C. glabrata, and C. parapsilosis, including ATCC and clinically isolated strains, was assessed for all compounds. The most active compound was N-benzyl-5-(3,4-dichlorophenyl)furan-2-carboxamide (6), with fungistatic and fungicidal effects against C. glabrata and C. parapsilosis strains (MIC = 0.062\u20130.125 and 0.125\u20130.250 mg\/mL, respectively). No synergistic effects were observed when combined with fluconazole. Interestingly, fluorescent microscopy analysis after staining with SYTO 9 and propidium iodide revealed that compound 6 affected the cell membrane integrity in C. albicans strain 16. Finally, carboxamide 6 exhibited a dose-dependent cytotoxicity on erythrocytes, based on assessing the LDH release.<\/jats:p>","DOI":"10.3390\/microorganisms13081835","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T13:25:11Z","timestamp":1754486711000},"page":"1835","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synthesis and Antifungal Evaluation Against Candida spp. of 5-Arylfuran-2-Carboxamide Derivatives"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-1882-5016","authenticated-orcid":false,"given":"Salvatore","family":"Mirabile","sequence":"first","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno D\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanna","family":"Ginestra","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno D\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3474-6057","authenticated-orcid":false,"given":"Rosamaria","family":"Pennisi","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno D\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1463-4069","authenticated-orcid":false,"given":"Davide","family":"Barreca","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno D\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5663-3702","authenticated-orcid":false,"given":"Giuseppina","family":"Mandalari","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno D\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosaria","family":"Gitto","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno D\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e428","DOI":"10.1016\/S1473-3099(23)00692-8","article-title":"Global incidence and mortality of severe fungal disease","volume":"24","author":"Denning","year":"2024","journal-title":"Lancet Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"18026","DOI":"10.1038\/nrdp.2018.26","article-title":"Invasive candidiasis","volume":"4","author":"Pappas","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1093\/jac\/dkad139","article-title":"Invasive candidiasis: Current clinical challenges and unmet needs in adult populations","volume":"78","author":"Soriano","year":"2023","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1038\/s41579-023-00960-9","article-title":"The rapid emergence of antifungal-resistant human-pathogenic fungi","volume":"21","author":"Lockhart","year":"2023","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1080\/21505594.2021.2019950","article-title":"Pathogenesis and virulence of Candida albicans","volume":"13","author":"Lopes","year":"2022","journal-title":"Virulence"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e470","DOI":"10.1016\/S2666-5247(23)00067-8","article-title":"Worldwide emergence of fluconazole-resistant Candida parapsilosis: Current framework and future research roadmap","volume":"4","author":"Daneshnia","year":"2023","journal-title":"Lancet Microbe"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Czajka, K.M., Venkataraman, K., Brabant-Kirwan, D., Santi, S.A., Verschoor, C., Appanna, V.D., Singh, R., Saunders, D.P., and Tharmalingam, S. (2023). Molecular Mechanisms Associated with Antifungal Resistance in Pathogenic Candida Species. Cells, 12.","DOI":"10.3390\/cells12222655"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1021\/acsinfecdis.4c00477","article-title":"Candida glabrata: A Tale of Stealth and Endurance","volume":"11","author":"Askari","year":"2025","journal-title":"ACS Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"100063","DOI":"10.1016\/j.tcsw.2021.100063","article-title":"Prospects for anti-Candida therapy through targeting the cell wall: A mini-review","volume":"7","author":"Ahmadipour","year":"2021","journal-title":"Cell Surf."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1021\/acsinfecdis.4c00657","article-title":"Mechanisms of Azole Potentiation: Insights from Drug Repurposing Approaches","volume":"11","author":"Xiong","year":"2025","journal-title":"ACS Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Shekhawat, D., Gouthami, K., Santra, A., Maity, S., Nagajyothi, P.C., Shim, J., and Reddy, V.D. (2025). A Comprehensive Review of Antimicrobial Drugs: Mechanisms of Action and Specific Targets in Microorganisms. J. Basic. Microbiol.","DOI":"10.1002\/jobm.70057"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6295","DOI":"10.1038\/s41467-025-61678-1","article-title":"Distinct echinocandin responses of Candida albicans and Candida auris cell walls revealed by solid-state NMR","volume":"16","author":"Singh","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1007\/s40265-021-01611-0","article-title":"The Antifungal Pipeline: Fosmanogepix, Ibrexafungerp, Olorofim, Opelconazole, and Rezafungin","volume":"81","author":"Hoenigl","year":"2021","journal-title":"Drugs"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"12429","DOI":"10.1021\/acs.jmedchem.0c00748","article-title":"Recent Progress in the Discovery of Antifungal Agents Targeting the Cell Wall","volume":"63","author":"Liu","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1021\/acsinfecdis.4c00828","article-title":"Recent Advances in the Development of Antifungal Agents: Beyond Azoles, Polyenes, and Echinocandins","volume":"11","author":"Saini","year":"2025","journal-title":"ACS Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3390","DOI":"10.1021\/acs.chemrev.0c00199","article-title":"Antifungal Drug Resistance: Molecular Mechanisms in Candida albicans and Beyond","volume":"121","author":"Lee","year":"2021","journal-title":"Chem. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ginestra, G., Gervasi, T., Mancuso, F., Bucolo, F., De Luca, L., Gitto, R., Barreca, D., and Mandalari, G. (2023). Evaluation of the In Vitro Antifungal Activity of Novel Arylsulfonamides against Candida spp. Microorganisms 2023, 11, 1522. Microorganisms, 11.","DOI":"10.3390\/microorganisms11061522"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Gervasi, T., Ginestra, G., Mancuso, F., Barreca, D., De Luca, L., and Mandalari, G. (2021). The In Vitro Potential of 1-(1H-indol-3-yl) Derivatives against Candida spp. and Aspergillus niger as Tyrosinase Inhibitors. Microorganisms, 9.","DOI":"10.3390\/microorganisms9102070"},{"key":"ref_19","unstructured":"CLSI (2017). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts, Clinical and Laboratory Standards Institute (CLSI). M27-A3."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1914","DOI":"10.1128\/AAC.40.8.1914","article-title":"Comparison of three different in vitro methods of detecting synergy: Time-kill, checkerboard, and E test","volume":"40","author":"White","year":"1996","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e202200305","DOI":"10.1002\/cmdc.202200305","article-title":"Design, Synthesis, and in Vitro Evaluation of 4-(4-Hydroxyphenyl)piperazine-Based Compounds Targeting Tyrosinase","volume":"17","author":"Mirabile","year":"2022","journal-title":"ChemMedChem"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1128\/AAC.42.8.2002","article-title":"Activities of three quinolones, alone and in combination with extended-spectrum cephalosporins or gentamicin, against Stenotrophomonas maltophilia","volume":"42","author":"Visalli","year":"1998","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Luo, J., and Raval, R. (2025). Correlative Imaging and super resolution microscopy studies reveal complexities in determining live-dead state of bacteria. Biofilm, 10.","DOI":"10.1016\/j.bioflm.2025.100302"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1021\/acs.chemrestox.3c00339","article-title":"Cell via Cell Viability Assay Changes Cellular Metabolic Characteristics by Intervening with Glycolysis and Pentose Phosphate Pathway","volume":"37","author":"Fan","year":"2024","journal-title":"Chem. Res. Toxicol."}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/13\/8\/1835\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:24:42Z","timestamp":1760034282000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/13\/8\/1835"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,6]]},"references-count":24,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["microorganisms13081835"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms13081835","relation":{},"ISSN":["2076-2607"],"issn-type":[{"type":"electronic","value":"2076-2607"}],"subject":[],"published":{"date-parts":[[2025,8,6]]}}}