{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:40:58Z","timestamp":1792456858742,"version":"4.5.0"},"reference-count":58,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,3,25]],"date-time":"2020-03-25T00:00:00Z","timestamp":1585094400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Frequent fungal infections in immunocompromised patients and mortality due to invasive mycosis are important clinical problems. Opportunistic pathogenic Candida species remain one of the leading causes of systemic mycosis worldwide. The repertoire of antifungal chemotherapeutic agents is very limited. Although new antifungal drugs such as lanosterol 14\u03b1-demethylase and \u03b2-glucan synthase inhibitors have been introduced into clinical practice, the development of multidrug resistance has become increasingly significant. The urgency to expand the range of therapeutic options for the treatment of fungal infections has led researchers in recent decades to seek alternative antifungal targets to the conventional ones currently used. Among them, many compounds containing an acridine scaffold have been synthesized and tested. In this review, the applicability of acridines and their functional analogues acridones as antifungal agents is described. Acridine derivatives usage in photoantifungal chemotherapy, interactions with fungal transporters resulting in modulation of efflux\/influx pumps and the effect of acridine derivatives on fungal topoisomerases are discussed. This article explores new perspectives on the mechanisms of antifungal acridine-peptide conjugates and acridine-based hybrid molecules to effectively combat fungal infections.<\/jats:p>","DOI":"10.3390\/molecules25071480","type":"journal-article","created":{"date-parts":[[2020,4,3]],"date-time":"2020-04-03T05:55:16Z","timestamp":1585893316000},"page":"1480","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["\u2018Acridines\u2019 as New Horizons in Antifungal Treatment"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0833-5596","authenticated-orcid":false,"given":"Iwona","family":"Gabriel","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Technology and Biochemistry, Gda\u0144sk University of Technology, 80-233 Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/jac\/47.1.1","article-title":"Acridine-a neglected antibacterial chromophore","volume":"47","author":"Wainwright","year":"2001","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1128\/CMR.12.4.583","article-title":"Antifungal Activities of Antineoplastic Agents: Saccharomyces cerevisiae as a Model System to Study Drug Action","volume":"12","author":"Cardenas","year":"1999","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1248\/bpb.28.591","article-title":"FTR1335 is a novel synthetic inhibitor of Candida albicans N-myristoyltransferase with fungicidal activity","volume":"28","author":"Ebara","year":"2005","journal-title":"Biol. Pharm. Bull."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.1128\/AAC.49.5.2084-2092.2005","article-title":"Efficacy, plasma pharmacokinetics, and safety of icofungipen, an inhibitor of Candida isoleucyl-tRNA synthetase, in treatment of experimental disseminated candidiasis in persistently neutropenic rabbits","volume":"49","author":"Petraitiene","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1111\/1567-1364.12014","article-title":"Homoisocitrate dehydrogenase from Candida albicans: Properties, inhibition, and targeting by an antifungal pro-drug","volume":"13","author":"Gabriel","year":"2013","journal-title":"FEMS Yeast Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"14022","DOI":"10.3390\/molecules171214022","article-title":"Antifungal activity of homoaconitate and homoisocitrate analogs","volume":"17","author":"Milewska","year":"2012","journal-title":"Molecules"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1016\/j.chembiol.2008.07.013","article-title":"Structure-guided development of efficacious antifungal agents targeting Candida glabrata dihydrofolate reductase","volume":"15","author":"Liu","year":"2008","journal-title":"Chem. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.ijantimicag.2017.05.019","article-title":"Epidemiology of antifungal resistance in human pathogenic yeasts: Current viewpoint and practical recommendations for management","volume":"50","author":"Farmakiotis","year":"2017","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1039\/C8MD00384J","article-title":"Medicinal chemistry of acridine and its analogues","volume":"9","author":"Prasher","year":"2018","journal-title":"Med. Chem. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1128\/jb.90.2.481-494.1965","article-title":"Acriflavine induction of different kinds of \u201cpetite\u201d mitochondrial populations in Saccharomyces cerevisiae","volume":"90","author":"Avers","year":"1965","journal-title":"J. Bacteriol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1083\/jcb.34.2.489","article-title":"The loss of kinetoplastic DNA in two species of Trypanosomatidae treated with acriflavine","volume":"34","author":"Steinert","year":"1967","journal-title":"J. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1111\/j.1749-6632.2009.04682.x","article-title":"Acriflavine-mediated apoptosis and necrosis in yeast Candida utilis","volume":"1171","author":"Keyhani","year":"2009","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1007\/s11094-015-1181-4","article-title":"Synthesis, Characterization, and In Vitro Antimicrobial and Antifungal Activity of Novel Acridines","volume":"48","author":"Kaya","year":"2015","journal-title":"Pharm. Chem. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1007\/s11172-014-0564-0","article-title":"Synthesis of 2-(4-methyl-1,3-thiazol-5-yl) ethyl esters of acridone carboxylic acids and evaluation of their antibacterial activity","volume":"63","author":"Markovich","year":"2014","journal-title":"Russ. Chem. Bull."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Chen, R., Huo, L., Jaiswal, Y., Huang, J., Zhong, Z., Zhong, J., Williams, L., Xia, X., Liang, Y., and Yan, Z. (2019). Design, Synthesis, Antimicrobial, and Anticancer Activities of Acridine Thiosemicarbazides Derivatives. Molecules, 24.","DOI":"10.3390\/molecules24112065"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1111\/jam.14381","article-title":"A new acridone with antifungal properties against Candida spp. and dermatophytes, and antibiofilm activity against C. albicans","volume":"127","author":"Silva","year":"2019","journal-title":"J. Appl. Microbiol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Kulkarny, V.V., Chavez-Dozal, A., Rane, H.S., Jahng, M., Bernardo, S.M., Parra, K.J., and Lee, S.A. (2014). Quinacrine inhibits Candida albicans growth and filamentation at neutral pH. Antimicrob. Agents. Chemother., 58.","DOI":"10.1128\/AAC.03083-14"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Persinoti, G.F., de Aguiar Peres, N.T., Jacob, T.R., Rossi, A., V\u00eancio, R.Z., and Martinez-Rossi, N.M. (2014). RNA-sequencing analysis of Trichophyton rubrum transcriptome in response to sublethal doses of acriflavine. BMC Genomics, 15.","DOI":"10.1186\/1471-2164-15-S7-S1"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Kabir, M.A., Hussain, M.A., and Ahmad, Z. (2012). Candida albicans: A Model Organism for Studying Fungal Pathogens. ISRN Microbiol., 2012.","DOI":"10.5402\/2012\/538694"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Ramage, G., Rajendran, R., Sherry, L., and Williams, C. (2012). Fungal Biofilm Resistance. Int. J. Microbiol., 2012.","DOI":"10.1155\/2012\/528521"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.drudis.2008.11.013","article-title":"Targeting virulence: A new paradigm for antifungals","volume":"14","author":"Gauwerky","year":"2009","journal-title":"Drug Discov. Today"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.ijantimicag.2010.03.002","article-title":"\u2018Safe\u2019 photoantimicrobials for skin and soft-tissue infections","volume":"36","author":"Wainwright","year":"2010","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"91","DOI":"10.3390\/md8010091","article-title":"Antimicrobial photodynamic therapy: Study of bacterial recovery viability and potential development of resistance after treatment","volume":"8","author":"Tavares","year":"2010","journal-title":"Mar. Drugs"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1128\/AAC.00603-09","article-title":"In vitro resistance selection studies of RLP068\/Cl, a new Zn(II) phthalocyanine suitable for antimicrobial photodynamic therapy","volume":"54","author":"Giuliani","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.micres.2007.08.001","article-title":"Antifungal photodynamic therapy","volume":"163","author":"Donnelly","year":"2008","journal-title":"Microbiol. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/j.bmcl.2018.02.005","article-title":"Synthesis, spectroscopic studies and biological evaluation of acridine derivatives: The role of aggregation on the photodynamic efficiency","volume":"28","author":"Miravet","year":"2018","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3692","DOI":"10.1128\/AEM.00748-13","article-title":"Imidazoacridinone derivatives as efficient sensitizers in photoantimicrobial chemotherapy","volume":"79","author":"Taraszkiewicz","year":"2013","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Taraszkiewicz, A., Szewczyk, G., Sarna, T., Bielawski, K.P., and Nakonieczna, J. (2015). Photodynamic Inactivation of Candida albicans with Imidazoacridinones: Influence of Irradiance, Photosensitizer Uptake and Reactive Oxygen Species Generation. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0129301"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Bailly, C. (2012). Contemporary challenges in the design of topoisomerase II inhibitors for cancer chemotherapy. Chem. Rev., 112.","DOI":"10.1021\/cr200325f"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1200\/jco.2008.26.15_suppl.1055","article-title":"Phase II trial of C1311, a novel inhibitor of topoisomerase II in advanced breast cancer","volume":"26","author":"Capizzi","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Baltazar, L.M., Ray, A., Santos, D.A., Cisalpino, P.S., Friedman, A.J., and Nosanchuk, J.D. (2015). Antimicrobial photodynamic therapy: An effective alternative approach to control fungal infections. Front. Microbiol., 6.","DOI":"10.3389\/fmicb.2015.00202"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1146\/annurev.biochem.70.1.369","article-title":"DNA topoisomerases: Structure, function, and mechanism","volume":"70","author":"Champoux","year":"2001","journal-title":"Annu. Rev. Biochem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.2174\/0929867023369277","article-title":"Acridine derivatives as chemotherapeutic agents","volume":"9","author":"Denny","year":"2002","journal-title":"Curr. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"139","DOI":"10.2174\/187152007780058669","article-title":"Acridine and acridone derivatives, anticancer properties and synthetic methods: Where are we now?","volume":"7","author":"Belmont","year":"2007","journal-title":"Anti-Cancer Agents Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Wu, C.C., Li, Y.C., Wang, Y.R., Li, T.K., and Chan, N.L. (2013). On the structural basis and design guidelines for type II topoisomerase-targeting anticancer drugs. Nucleic Acids Res., 41.","DOI":"10.1093\/nar\/gkt828"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6034","DOI":"10.1093\/nar\/gki904","article-title":"Induction of unique structural changes in guanine-rich DNA regions by the triazoloacridone C-1305, a topoisomerase II inhibitor with antitumor activities","volume":"33","author":"Lemke","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4487","DOI":"10.1158\/0008-5472.CAN-03-3410","article-title":"Increased susceptibility of poly (ADP-ribose) polymerase-1 knockout cells to antitumor triazoloacridone C-1305 is associated with permanent G2 cell cycle arrest","volume":"64","author":"Schloffer","year":"2004","journal-title":"Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1021\/jm00163a009","article-title":"5-[(Aminoalkyl)amino]imidazo[4,5,1-de]acridin-6-ones as a novel class of antineoplastic agents. Synthesis and biological activity","volume":"33","author":"Cholody","year":"1990","journal-title":"J. Med. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1016\/S0006-2952(03)00477-5","article-title":"Molecular mechanism of the enzymatic oxidation investigated for imidazoacridinone antitumor drug, C-1311","volume":"66","author":"Mazerska","year":"2003","journal-title":"Biochem. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1016\/j.biopha.2018.04.021","article-title":"DNA gyrase inhibitors: Progress and synthesis of potent compounds as antibacterial agents","volume":"103","author":"Khan","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"7178","DOI":"10.1073\/pnas.82.21.7178","article-title":"Cloning of yeast TOP1, the gene encoding DNA topoisomerase I and DNA topoisomerase II","volume":"82","author":"Goto","year":"1985","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/S1054-3589(08)60542-6","article-title":"Roles of DNA topoisomerases in chromosomal replication and segregation","volume":"29A","author":"Nitiss","year":"1994","journal-title":"Adv. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/S0092-8674(85)80028-3","article-title":"DNA topoisomerase II is required at the time of mitosis in yeast","volume":"41","author":"Holm","year":"1985","journal-title":"Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1093\/genetics\/152.1.167","article-title":"Topoisomerase I is essential in Cryptococcus neoformans: Role in pathobiology and as an antifungal target","volume":"152","author":"Toffaletti","year":"1999","journal-title":"Genetics"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1099\/00221287-143-2-377","article-title":"The topoisomerase I gene from Candida albicans","volume":"143","author":"Jiang","year":"1997","journal-title":"Microbiology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"155","DOI":"10.3109\/13693780903114934","article-title":"In vitro effect of DNA topoisomerase inhibitors on Candida albicans","volume":"48","author":"Kwok","year":"2010","journal-title":"Med. Mycol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Steverding, D., Evans, P., Msika, L., Riley, B., Wallington, J., and Schelenz, S. (2012). In vitro antifungal activity of DNA topoisomerase inhibitors. Med. Mycol., 50.","DOI":"10.3109\/13693786.2011.609186"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2778","DOI":"10.1128\/AAC.36.12.2778","article-title":"DNA topoisomerases from pathogenic fungi: Targets for the discovery of antifungal drugs","volume":"36","author":"Shen","year":"1992","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1111\/j.1574-6968.1996.tb08142.x","article-title":"Comparison of responses of DNA topoisomerase I from Candida albicans and human cells to four new agents which stimulate topoisomerase-dependent DNA nicking","volume":"138","author":"Fostel","year":"1996","journal-title":"FEMS Microbiol. Lett."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.ejps.2017.08.027","article-title":"Amino acid or peptide conjugates of acridine\/acridone and quinoline\/quinolone-containing drugs. A critical examination of their clinical effectiveness within a twenty-year time frame in antitumor chemotherapy and treatment of infectious diseases","volume":"109","author":"Kukowska","year":"2017","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/S1074-5521(03)00147-9","article-title":"Preferred RNA binding sites for a threading intercalator revealed by in vitro evolution","volume":"10","author":"Carlson","year":"2003","journal-title":"Chem. Biol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Qi, X., Xia, T., and Roberts, R.W. (2010). Acridine-N peptide conjugates display enhanced affinity and specificity for boxB RNA targets. Biochemistry, 49.","DOI":"10.1021\/bi100634h"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"500","DOI":"10.15302\/J-ENG-2015106","article-title":"Conjugation with acridines turn nuclear localization sequence into highly active antimicrobial peptide","volume":"1","author":"Zhang","year":"2015","journal-title":"Engineering"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1021\/acsmedchemlett.7b00119","article-title":"Branched Peptides: Acridine and Boronic Acid Derivatives as Antimicrobial Agents","volume":"8","author":"Wynn","year":"2017","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"4057","DOI":"10.1128\/AAC.01648-07","article-title":"Enhanced susceptibility to antifungal oligopeptides in yeast strains overexpressing ABC multidrug efflux pumps","volume":"52","author":"Wakiec","year":"2008","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/S0074-7696(04)42005-1","article-title":"Multidrug resistance in yeast Candida","volume":"242","author":"Prasad","year":"2005","journal-title":"Int. Rev. Cytol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3973","DOI":"10.1016\/j.bmc.2009.04.026","article-title":"Design, synthesis and evaluations of acridone derivatives using Candida albicans-search for MDR modulators led to the identification of an anti-candidiasis agent","volume":"17","author":"Singh","year":"2009","journal-title":"Bioorg. Med. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"4212","DOI":"10.1016\/j.bmc.2010.05.003","article-title":"Targeting efflux pumps-In vitro investigations with acridone derivatives and identification of a lead molecule for MDR modulation","volume":"18","author":"Singh","year":"2010","journal-title":"Bioorg. Med. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/7\/1480\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:11:25Z","timestamp":1760173885000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/7\/1480"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,25]]},"references-count":58,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["molecules25071480"],"URL":"https:\/\/doi.org\/10.3390\/molecules25071480","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,25]]}}}