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In this study, a series of juglone-derived naphthoquinone analogs was synthesized to explore the influence of substitution pattern on anti-inflammatory activity and cytotoxicity. Their biological profiles were first evaluated in LPS-stimulated HaCaT cells by combining cytotoxicity assessment with nitric oxide (NO) screening. Most derivatives showed reduced cytotoxicity compared with juglone, and preliminary structure\u2013activity relationship analysis indicated that retention of a free hydroxyl group at the C-2 position was generally favorable for both reduction in NO release and cellular safety, whereas C-3 alkyl substitution tended to weaken activity and increase cytotoxicity. Among the tested compounds, compound 11 showed the most favorable balance between reduction in NO release and low cytotoxicity. Further evaluation showed that compound 11 reduced the protein levels of several inflammatory mediators in the culture supernatants of LPS-stimulated HaCaT cells, including TNF-\u03b1, IL-6, IL-1\u03b2, IL-17A, and IL-23, under the tested conditions. In an imiquimod-induced psoriasis-like mouse model, topical administration of compound 11 partially alleviated IMQ-induced psoriasis-like skin lesions, improved histopathological changes to some extent, and reduced selected inflammatory cytokine levels in serum and skin tissues under the tested conditions. Exploratory target prediction, molecular docking, and in silico ADMET analyses provided supportive computational insight into the biological profile of compound 11. Overall, these findings suggest that juglone-derived naphthoquinones may serve as useful natural-product-inspired scaffolds for further anti-inflammatory optimization, and compound 11 warrants further investigation in psoriasis-related experimental models.<\/jats:p>","DOI":"10.3390\/biom16060802","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T01:08:02Z","timestamp":1780535282000},"page":"802","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Synthesis, Biological Evaluation and Structure\u2013Activity Relationship of Juglone Derived Naphthoquinones as Potential Antipsoriatic Agents"],"prefix":"10.3390","volume":"16","author":[{"given":"Tong","family":"Bu","sequence":"first","affiliation":[{"name":"College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 730000, China"},{"name":"Key Laboratory of New Animal Drug Project, Gansu Province, Key Laboratory of Veterinary 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