{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T19:37:04Z","timestamp":1789760224701,"version":"4.0.1"},"reference-count":43,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T00:00:00Z","timestamp":1734566400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009687","name":"Wroclaw Medical University","doi-asserted-by":"publisher","award":["SUBK.D090.23.007"],"award-info":[{"award-number":["SUBK.D090.23.007"]}],"id":[{"id":"10.13039\/501100009687","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Microbiological communities have a significant impact on health and disease. Candida are ubiquitous fungal pathogens that colonize the mucosal surfaces of the genital, urinary, respiratory, and gastrointestinal tracts, as well as the oral cavity. If the immune system is inadequate, then Candida infections may pose a significant threat. Due to the limited number of clinically approved drugs for the treatment of Candida albicans-based infections and the rapid emergence of resistance to the existing antifungals, a novel series of isoxazole-based derivatives was synthesized and evaluated in vitro for their anti-Candida potential. Two compounds, PUB14 and PUB17, displayed selective antifungal activity without negatively affecting beneficial microbiota, such as Lactobacillus sp., at the same time. Moreover, these compounds exhibited significantly lower cytotoxicity in comparison to conventionally applied local antimicrobial (octenidine dihydrochloride), indicating their potential for safe and effective clinical application in conditions such as vulvovaginal candidiasis. The selective antifungal activity of PUB14 and PUB17 against C. albicans, coupled with its absence of antibacterial effects and minimal cytotoxicity towards HeLa cells, suggests a targeted mechanism of action that warrants further investigation. Consideration of the need to search for new antifungal agents and the discovery of an antifungal potential drug that does not inhibit lactobacilli growth could be a potential strategy to prevent and combat vulvovaginal candidiasis. This striking capacity to eradicate biofilm formed by Candida reveals a new approach to eradicating biofilms and sheds light on isoxazole-based derivatives as promising anti-biofilm drugs.<\/jats:p>","DOI":"10.3390\/ijms252413618","type":"journal-article","created":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T10:54:20Z","timestamp":1734605660000},"page":"13618","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Novel Isoxazole-Based Antifungal Drug Candidates"],"prefix":"10.3390","volume":"25","author":[{"given":"Urszula","family":"B\u0105chor","sequence":"first","affiliation":[{"name":"Department of Organic Chemistry and Drug Technology, Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9520-3377","authenticated-orcid":false,"given":"Malwina","family":"Bro\u017cyna","sequence":"additional","affiliation":[{"name":"Unique Application Model Laboratory, Department of Pharmaceutical Microbiology and Parasitology, Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7559-8903","authenticated-orcid":false,"given":"Adam","family":"Junka","sequence":"additional","affiliation":[{"name":"Unique Application Model Laboratory, Department of Pharmaceutical Microbiology and Parasitology, Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5364-6556","authenticated-orcid":false,"given":"Mateusz Ramires","family":"Chmielarz","sequence":"additional","affiliation":[{"name":"Department of Clinical Microbiology, Faculty of Medicine, Wroclaw Medical University, Chalubinskiego 4, 50-368 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5328-2927","authenticated-orcid":false,"given":"Damian","family":"Gorczyca","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Lazarski University, 02-662 Warszawa, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6110-344X","authenticated-orcid":false,"given":"Marcin","family":"M\u0105czy\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry and Drug Technology, Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1007\/s00044-018-2146-4","article-title":"Evaluation of Triazole and Isoxazole Derivatives as Potential Anti-infective Agents","volume":"27","author":"Tarawneh","year":"2018","journal-title":"Med. Chem. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.2147\/IDR.S175588","article-title":"Efficacy of antifungal drugs in the treatment of vulvovaginal candidiasis: A Bayesian network meta-analysis","volume":"17","author":"Qin","year":"2018","journal-title":"Infect. Drug Resist."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.jhin.2016.08.004","article-title":"Multidrug-resistant Candida auris: \u2018new kid on the block\u2019 in hospital-associated infections?","volume":"94","author":"Chowdhary","year":"2016","journal-title":"J. Hosp. Infect."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1099\/jmm.0.000082","article-title":"Antifungal activity of clotrimazole against Candida albicans depends on carbon sources, growth phase, and morphology","volume":"64","author":"Kasper","year":"2015","journal-title":"J. Med. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3065","DOI":"10.1016\/j.bmc.2018.05.013","article-title":"The recent progress of isoxazole in medicinal chemistry","volume":"26","author":"Zhu","year":"2018","journal-title":"Bioorg. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1016\/0029-7844(95)00318-L","article-title":"Effect of Candida albicans infection and clotrimazole treatment on vaginal microflora in vitro","volume":"86","author":"Ross","year":"1995","journal-title":"Obstet. Gynecol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1111\/myc.12485","article-title":"The efficacy and safety of clotrimazole vaginal tablet vs. oral fluconazole in treating severe vulvovaginal candidiasis","volume":"59","author":"Zhou","year":"2016","journal-title":"Mycoses"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Strzelecka, M., Wiatrak, B., Jawie\u0144, P., Czy\u017cnikowska, \u017b., and \u015awi\u0105tek, P. (2023). New Schiff bases derived from dimethylpyridine-1,2,4-triazole hybrid as cytotoxic agents targeting gastrointestinal cancers: Design, synthesis, biological evaluation and molecular docking studies. Bioorg. Chem., 139.","DOI":"10.1016\/j.bioorg.2023.106758"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Mikus, J., \u015awi\u0105tek, P., Przyby\u0142a, P., Krzy\u017cak, E., Marciniak, A., Kotynia, A., Redzicka, A., Wiatrak, B., Jawie\u0144, P., and G\u0119barowski, T. (2023). Synthesis, Biological, Spectroscopic and Computational Investigations of Novel N-Acylhydrazone Derivatives of Pyrrolo[3,4-d]pyridazinone as Dual COX\/LOX Inhibitors. Molecules, 28.","DOI":"10.3390\/molecules28145479"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Kotynia, A., Krzy\u017cak, E., \u017b\u0105d\u0142o, J., Witczak, M., Szczukowski, \u0141., Mucha, J., \u015awi\u0105tek, P., and Marciniak, A. (2024). Anti-Inflammatory and Antioxidant Pyrrolo[3,4-d]pyridazinone Derivatives Interact with DNA and Bind to Plasma Proteins\u2014Spectroscopic and In Silico Studies. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25031784"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Dudek, B., B\u0105chor, U., Drozd-Szczygie\u0142, E., Bro\u017cyna, M., D\u0105browski, P., Junka, A., and M\u0105czy\u0144ski, M. (2023). Antimicrobial and Cytotoxic Activities of Water-Soluble Isoxazole-Linked 1,3,4-Oxadiazole with Delocalized Charge: In Vitro and In Vivo Results. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242216033"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"29668","DOI":"10.1039\/D1RA05116D","article-title":"New water-soluble isoxazole-linked 1,3,4-oxadiazole derivative with delocalized positive charge","volume":"11","author":"Jerzykierwicz","year":"2021","journal-title":"RSC Adv."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"B\u0105chor, U., Lizak, A., B\u0105chor, R., and M\u0105czy\u0144ski, M. (2022). 5-Amino-3-methyl-Isoxazole-4-carboxylic Acid as a Novel Unnatural Amino Acid in the Solid Phase Synthesis of \u03b1\/\u03b2-Mixed Peptides. Molecules, 27.","DOI":"10.3390\/molecules27175612"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Sochacka-\u0106wik\u0142a, A., M\u0105czy\u0144ski, M., Czy\u017cnikowska, \u017b., Wiatrak, B., J\u0119\u015bkowiak, I., Czerski, A., and Regiec, A. (2022). New oxazolo[5,4-d]pyrimidines as potential anticancer agents: Their design, synthesis, and in vitro biological activity research. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911694"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"M\u0105czy\u0144ski, M., Regiec, A., Sochacka-\u0106wik\u0142a, A., Kochanowska, I., Koci\u0119ba, M., Zaczy\u0144ska, E., Artym, J., Ka\u0142as, W., and Zimecki, M. (2021). Synthesis, Physicochemical Characteristics and Plausible Mechanism of Action of an Immunosuppressive Isoxazolo[5,4-e]-1,2,4-Triazepine Derivative (RM33). Pharmaceuticals, 14.","DOI":"10.3390\/ph14050468"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Sochacka-\u0106wik\u0142a, A., Regiec, A., Zimecki, M., Artym, J., Zaczy\u0144ska, E., Koci\u0119ba, M., Kochanowska, I., Bryndal, I., Pyra, A., and M\u0105czy\u0144ski, M. (2020). Synthesis and Biological Activity of New 7-Amino-oxazolo[5,4-d]Pyrimidine Derivatives. Molecules, 25.","DOI":"10.3390\/molecules25153558"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"B\u0105chor, U., Junka, A., Bro\u017cyna, M., and M\u0105czy\u0144ski, M. (2023). The In Vitro Impact of Isoxazole Derivatives on Pathogenic Biofilm and Cytotoxicity of Fibroblast Cell Line. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032997"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6355","DOI":"10.1007\/s00253-021-11477-7","article-title":"The newly synthesized thiazole derivatives as potential antifungal compounds against Candida albicans","volume":"105","author":"Biernasiuk","year":"2021","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Lisa, E.L., Dragostin, O.M., Petroaie, A.D., Gurau, G., Cristea, A., Pavel, A., Bonifate, F., Popa, P.S., and Matei, M. (2022). The Effect of the New Imidazole Derivatives Complexation with Betacyclodextrin, on the Antifungal Activity in Oropharyngeal Infections. Processes, 10.","DOI":"10.3390\/pr10122697"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Kondrashov, E.V., Belovezhets, L.A., Shatokhina, N.S., Shilova, A.N., Kostyro, Y.A., Markova, Y.A., Borovskaya, M.K., and Borovskii, G.B. (2023). Design of novel water-soluble isoxazole-based antimicrobial agents and evaluation of their cytotoxicity and acute toxicity. Bioorg. Chem., 138.","DOI":"10.1016\/j.bioorg.2023.106644"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.ejmech.2016.09.093","article-title":"Novel pyrazolo [3,4-d]pyrimidine with 4-(1H-benzimidazol-2-yl)-phenylamine as broad spectrum anticancer agents: Synthesis, cell based assay, topoisomerase inhibition, DNA intercalation and bovine serum albumin studies","volume":"126","author":"Singla","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.ejmech.2018.03.083","article-title":"Synthesis, molecular modeling studies and evaluation of antifungal activity of a novel series of thiazole derivatives","volume":"151","author":"Lino","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/j.ejmech.2015.04.015","article-title":"Recent applications of 1,3-thiazole core structure in the identification of new lead compounds and drug discovery","volume":"97","author":"Ayati","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Petrou, A., Fesatidou, M., and Geronikaki, A. (2021). Thiazole Ring\u2014A Biologically Active Scaffold. Molecules, 26.","DOI":"10.3390\/molecules26113166"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1016\/j.ejmech.2010.10.027","article-title":"Synthesis and Biological Evaluation of Novel 2,4-Disubstituted-1,3-thiazoles as Anti-Candida spp. Agents","volume":"46","author":"Chimenti","year":"2010","journal-title":"Eur. J. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Pricopie, A.I., Ionu\u021b, I., Marc, G., Arseniu, A.M., Vlase, L., Grozav, A., G\u0103in\u0103, L.I., Vodnar, D.C., P\u00eern\u0103u, A., and Tiperciuc, B. (2019). Design and Synthesis of Novel 1,3-Thiazole and 2-Hydrazinyl-1,3-Thiazole Derivatives as Anti-Candida Agents: In Vitro Antifungal Screening, Molecular Docking Study, and Spectroscopic Investigation of their Binding Interaction with Bovine Serum Albumin. Molecules, 24.","DOI":"10.3390\/molecules24193435"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1021\/acs.jafc.8b06935","article-title":"Discovery of novel thiazole carboxamides as antifungal succinate dehydrogenase inhibitors","volume":"67","author":"Guo","year":"2019","journal-title":"J. Agric. Food Chem."},{"key":"ref_28","unstructured":"Regiec, A., and Gadzi\u0144ski, P. (2014). New Methods for Preparing of Esters of 2-cyano-3-alkoxy-2-butenoate Acids. (PL 216770, B1), Polish Patent."},{"key":"ref_29","unstructured":"Regiec, A., Gadzi\u0144ski, P., and P\u0142oszaj, P. (2014). New Methods for Preparing of Esters of 5-Amino-3-methyl-4-isoxazolecarboxylic Acid. (PL 216764 B1), Polish Patent."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"343","DOI":"10.4155\/fmc-2021-0275","article-title":"Antibacterial pyrazoles: Tackling resistant bacteria","volume":"14","author":"Alam","year":"2022","journal-title":"Future Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Burke, A., Di Filippo, M., Spiccio, S., Schito, A.M., Caviglia, D., Brullo, C., and Baumann, M. (2023). Antimicrobial Evaluation of New Pyrazoles, Indazoles and Pyrazolines Prepared in Continuous Flow Mode. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24065319"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Sayed, M.T., Elsharabasy, S.A., and Abdel-Aziem, A. (2023). Synthesis and antimicrobial activity of new series of thiazoles, pyridines and pyrazoles based on coumarin moiety. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-36705-0"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Ambade, S.S., Gupta, V.K., Bhole, R.P., Khedekar, P.B., and Chikhale, R.V. (2023). A Review on Five and Six-Membered Heterocyclic Compounds Targeting the Penicillin-Binding Protein 2 (PBP2A) of Methicillin-Resistant Staphylococcus aureus (MRSA). Molecules, 28.","DOI":"10.20944\/preprints202309.0856.v1"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1016\/j.bmcl.2013.01.039","article-title":"Synthesis and anti-Candida activity of novel 2-hydrazino-1,3-thiazole derivatives","volume":"23","author":"Maillard","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.jscs.2017.04.007","article-title":"Synthesis of 2-phenylamino-thiazole derivatives as antimicrobial agents","volume":"21","author":"Bikobo","year":"2017","journal-title":"J. Saudi Chem. Soc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1080\/21505594.2016.1188236","article-title":"The Synthesis, Regulation, and Functions of Sterols in Candida albicans: Well-Known but Still Lots to Learn","volume":"7","author":"Lv","year":"2016","journal-title":"Virulence"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e01755-18","DOI":"10.1128\/mBio.01755-18","article-title":"The Multifunctional Fungal Ergosterol","volume":"9","author":"Rodrigues","year":"2018","journal-title":"mBio"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Nikookar Golestani, R., Ghods, E., Rostamian, M., Madanchi, H., and Talebi, A.F. (2023). Investigating the antimicrobial activity, cytotoxicity, and action mechanism of acylated and amidated derivatives of AurH1 antifungal peptide. BMC Microbiol., 23.","DOI":"10.1186\/s12866-023-03090-7"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1007\/s00210-021-02059-5","article-title":"Sertaconazole induced toxicity in HeLa cells through mitotic arrest and inhibition of microtubule assembly","volume":"394","author":"Sebastian","year":"2021","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Turecka, K., Chylewska, A., Kawiak, A., and Waleron, K.F. (2018). Antifungal Activity and Mechanism of Action of the Co(III) Coordination Complexes With Diamine Chelate Ligands Against Reference and Clinical Strains of Candida spp. Front. Microbiol., 9.","DOI":"10.3389\/fmicb.2018.01594"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"W5","DOI":"10.1093\/nar\/gkab255","article-title":"ADMETlab 2.0: An integrated online platform for accurate and comprehensive predictions of ADMET properties","volume":"49","author":"Xiong","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Krasowski, G., Migda\u0142, P., Woroszy\u0142o, M., Fija\u0142kowski, K., Chodaczek, G., Czajkowska, J., Dudek, B., Nowicka, J., Oleksy-Wawrzyniak, M., and Kwiek, B. (2022). The Assessment of Activity of Antiseptic Agents against Biofilm of Staphylococcus aureus Measured with the Use of Processed Microscopic Images. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232113524"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1038\/nprot.2008.75","article-title":"Neutral red uptake assay for the estimation of cell viability\/cytotoxicity","volume":"3","author":"Repetto","year":"2008","journal-title":"Nat Protoc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/24\/13618\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:55:43Z","timestamp":1760115343000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/24\/13618"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,19]]},"references-count":43,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["ijms252413618"],"URL":"https:\/\/doi.org\/10.3390\/ijms252413618","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,19]]}}}