{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T18:32:07Z","timestamp":1762367527732,"version":"build-2065373602"},"reference-count":25,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T00:00:00Z","timestamp":1762300800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Histone deacetylases (HDACs) mediate the removal of acetyl groups from lysine residues in both histone and non-histone proteins, and have been regarded as promising targets for drug discovery. As a central member of HDAC family, HDAC1 has been found to be closely linked to the occurrence and development of prostate cancer. In this study, we designed and synthesized a new series of 3-phenylisoxazole HDAC1 inhibitors based on the hit\n                    <jats:bold>7<\/jats:bold>\n                    , identified by in-house compound library screening. The structure-activity relationship studies (SARs) indicated that the R\n                    <jats:sub>1<\/jats:sub>\n                    position was relatively tolerated for activity. The linker length at R\n                    <jats:sub>2<\/jats:sub>\n                    exerted a significant influence on activity with the relative orders of butyl\u2009&gt;\u2009propyl\u2009&gt;\u2009ethyl\u2009&gt;\u2009methyl. Among synthetic 16 compounds, compound\n                    <jats:bold>17<\/jats:bold>\n                    indicated the strongest HDAC1 inhibitory effect with the inhibition rate of 86.78% at the concentration of 1000 nM. In addition, derivative\n                    <jats:bold>17<\/jats:bold>\n                    could not only well occupy the active pocket of HDAC1, but also showed favorable drug-like properties. More importantly, molecule\n                    <jats:bold>17<\/jats:bold>\n                    exerted potent anti-proliferative activity on prostate cancer PC3 cells with the IC\n                    <jats:sub>50<\/jats:sub>\n                    value of 5.82 \u03bcM, and had no significant toxicity against normal prostate WPMY-1 cells. Collectively, these findings validate phenylisoxazole derivative\n                    <jats:bold>17<\/jats:bold>\n                    as a promising lead compound for further optimization and development.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0334632","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T18:29:06Z","timestamp":1762367346000},"page":"e0334632","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design, synthesis, and biological evaluation of phenylisoxazole-based histone deacetylase 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