{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T15:31:15Z","timestamp":1786375875076,"version":"build-2736575974"},"reference-count":56,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["24-14-00081"],"award-info":[{"award-number":["24-14-00081"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"award":["24-14-00081"],"award-info":[{"award-number":["24-14-00081"]}],"id":[{"id":"https:\/\/ror.org\/03y2gwe85","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: The emergence of antifungal resistance and the limited number of clinically available antifungal drug classes necessitate the development of new agents with improved efficacy and safety. We investigated how linker architecture influences the antifungal activity and lead properties of hybrid triazole-thiazolidine derivatives. Methods: A focused library of triazole-thiazolidine hybrids incorporating alkylamine, amide, cyclic amine, 2-hydroxypropyl, and thiazepane linkers was synthesized and characterized. Antifungal activity was evaluated against reference strains and clinical isolates of Candida spp., Aspergillus fumigatus, dermatophytes, and Cryptococcus neoformans. Structure\u2013activity relationships were analyzed by molecular docking. Selected compounds were further assessed by SCRAPPY profiling, fluorescence microscopy, mammalian-cell cytotoxicity assays, acute oral toxicity studies, and evaluation of microsomal stability and interactions with human CYP450 isoforms. Results: Linker architecture strongly influenced antifungal potency. Amide- and cyclic amine-containing hybrids were generally the most active, whereas simple alkylamide derivatives showed narrower activity profiles. Compound 28 emerged as the most promising lead, exhibiting sub-microgram MIC values against several Candida isolates, particularly C. parapsilosis, and retaining measurable activity against an azole-resistant C. albicans strain. Docking generated putative CYP51-binding models, while SCRAPPY profiling and fluorescence microscopy revealed an azole-like cellular response consistent with perturbation of sterol-associated homeostasis. Compound 28 was tolerated at 300 mg\/kg in an acute oral study but showed concentration- and time-dependent cytotoxicity and rapid CYP3A4-mediated microsomal metabolism. Conclusions: Systematic variation of linker architecture identified compound 28 as a promising exploratory antifungal lead. Further optimization should focus on improving metabolic stability and cytotoxicity, together with direct target validation, pharmacokinetic characterization, and in vivo efficacy studies.<\/jats:p>","DOI":"10.3390\/ph19081260","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T15:10:24Z","timestamp":1786374624000},"page":"1260","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Linker Engineering of Hybrid Triazole-Thiazolidine Antifungals Identifies a Promising Lead Against Drug-Resistant Candida Species"],"prefix":"10.3390","volume":"19","author":[{"given":"Alexander Yu.","family":"Rudenko","sequence":"first","affiliation":[{"name":"Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, 119991 Moscow, Russia"},{"name":"Chemical Department, M.V. Lomonosov Moscow State University, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga A.","family":"Komarova","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya 16\/10, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander Yu.","family":"Simonov","sequence":"additional","affiliation":[{"name":"Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, 119021 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2328-7162","authenticated-orcid":false,"given":"Ratislav M.","family":"Ozhiganov","sequence":"additional","affiliation":[{"name":"Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, 119991 Moscow, Russia"},{"name":"Chemical Department, M.V. Lomonosov Moscow State University, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitrii A.","family":"Averianov","sequence":"additional","affiliation":[{"name":"Chemical Department, M.V. Lomonosov Moscow State University, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofiia R.","family":"Kuklich","sequence":"additional","affiliation":[{"name":"Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1818-6590","authenticated-orcid":false,"given":"Ekaterina A.","family":"Guseva","sequence":"additional","affiliation":[{"name":"Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, 119991 Moscow, Russia"},{"name":"Chemical Department, M.V. Lomonosov Moscow State University, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofya Y.","family":"Sokolskaya","sequence":"additional","affiliation":[{"name":"Faculty of Fundamental Medicine, M.V. Lomonosov Moscow State University, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyudmila G.","family":"Kuz\u2019mina","sequence":"additional","affiliation":[{"name":"N.S. Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3508-231X","authenticated-orcid":false,"given":"Natalia E.","family":"Grammatikova","sequence":"additional","affiliation":[{"name":"M.V. Lomonosov Institute of Fine Chemical Technologies, MIREA-Russian Technological University, 119571 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander B.","family":"Kulko","sequence":"additional","affiliation":[{"name":"Clinical Antituberculosis Center, Moscow Government Health Department Scientific, St. Stromynka, 10, 107014 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0883-7174","authenticated-orcid":false,"given":"Victoria A.","family":"Bidiuk","sequence":"additional","affiliation":[{"name":"Federal Research Center of Biotechnology of the RAS, 33-2 Leninsky Prospect, 119071 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9190-1298","authenticated-orcid":false,"given":"Sofia S.","family":"Mariasina","sequence":"additional","affiliation":[{"name":"Chemical Department, M.V. Lomonosov Moscow State University, 119991 Moscow, Russia"},{"name":"Institute of Pharmacy and Biotechnology, RUDN University, 117198 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9664-9506","authenticated-orcid":false,"given":"Vasiliy A.","family":"Ivlev","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy and Biotechnology, RUDN University, 117198 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8866-1863","authenticated-orcid":false,"given":"Peter V.","family":"Sergiev","sequence":"additional","affiliation":[{"name":"Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, 119991 Moscow, Russia"},{"name":"Chemical Department, M.V. Lomonosov Moscow State University, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3216-5737","authenticated-orcid":false,"given":"Vladimir I.","family":"Polshakov","sequence":"additional","affiliation":[{"name":"Chemical Department, M.V. Lomonosov Moscow State University, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey B.","family":"Mantsyzov","sequence":"additional","affiliation":[{"name":"Chemical Department, M.V. Lomonosov Moscow State University, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor B.","family":"Levshin","sequence":"additional","affiliation":[{"name":"Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, 119021 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (WHO) (2022). WHO Fungal Priority Pathogens List to Guide Research, Development and Public Health Action, World Health Organization."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.bcp.2016.11.019","article-title":"Antifungals","volume":"133","author":"Campoy","year":"2017","journal-title":"Biochem. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/s00253-023-12884-8","article-title":"Old and New Strategies in Therapy and Diagnosis against Fungal Infections","volume":"108","author":"Vanzolini","year":"2024","journal-title":"Appl. Microbiol. 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