{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T08:59:44Z","timestamp":1785488384898,"version":"3.56.0"},"reference-count":36,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Invasive and mucosal infections caused by Candida species continue to pose a significant global health burden, particularly due to the species\u2019 increasing resistance to conventional antifungal agents. This systematic review evaluates the antifungal potential of pyrrolidine-based derivatives, focusing on structure\u2013activity relationships, mechanisms of action, and activity against Candida species. Methods: A systematic literature search was conducted in PubMed, Scopus, and Web of Science for studies published between January 2015 and January 2026, following PRISMA guidelines and registered in PROSPERO (CRD420261279035). Studies reporting in vitro, in vivo, or in silico evaluation of pyrrolidine derivatives against Candida species were included. Data extraction and risk-of-bias assessment were performed using predefined criteria. Results: Twelve studies met the inclusion criteria, describing diverse pyrrolidine-based scaffolds, including spirooxindole, dispiro, triazole-linked, tetrazole, and quinoline-fused derivatives. The compounds demonstrated antifungal activity against multiple Candida species, including resistant isolates with minimum inhibitory concentrations ranging from approximately 0.5 to 16 \u00b5g\/mL. Several derivatives showed comparable activity to standard antifungal agents under the reported experimental conditions. Mechanistic investigations indicated inhibition of biofilm formation, disruption of fungal cell wall and membrane integrity, suppression of hyphal transition, and modulation of virulence-associated pathways. Multi-mechanism antifungal effects were reported across different structural classes. Conclusions: Pyrrolidine-based derivatives represent promising antifungal scaffolds with potent activity against Candida species and associated virulence factors. However, limited in vivo validation and insufficient pharmacokinetic and toxicity data remain major barriers to clinical translation. Further optimization of structure\u2013activity relationships and comprehensive preclinical evaluation are required to advance these scaffolds toward therapeutic development.<\/jats:p>","DOI":"10.3390\/ph19081198","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T08:20:18Z","timestamp":1785486018000},"page":"1198","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pyrrolidine-Based Antifungal Agents Against Candida Species: A Systematic Review of Structure\u2013Activity Relationships and Mechanistic Insights from Experimental Studies"],"prefix":"10.3390","volume":"19","author":[{"given":"Harinahalli Ganesh","family":"Sinchan","sequence":"first","affiliation":[{"name":"Department of Microbiology, School of Life Sciences, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagaraju","family":"Chaithra","sequence":"additional","affiliation":[{"name":"Division of Medical Statistics, School of Life Sciences, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0365-5080","authenticated-orcid":false,"given":"Shivaswamy","family":"Umamaheshwari","sequence":"additional","affiliation":[{"name":"Department of Microbiology, School of Life Sciences, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Acosta-Mosquera, Y., Tapia, J.C., Armas-Gonz\u00e1lez, R., Pazmi\u00f1o-Moncayo, K., Proa\u00f1o-Bola\u00f1os, C., Cevallos, M., Vizuete, K., Debut, A., and Vizuete, D. 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