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New acetamides <jats:bold>3<\/jats:bold>(<jats:bold>a\u2013c<\/jats:bold>) and <jats:bold>4<\/jats:bold>(<jats:bold>a\u2013c<\/jats:bold>) were synthesized and characterized as precursors for novel N\u2010aminophalimides <jats:bold>5<\/jats:bold>(<jats:bold>a\u2013c<\/jats:bold>) and <jats:bold>6<\/jats:bold>(<jats:bold>a\u2013c<\/jats:bold>). Structures of <jats:bold>4a<\/jats:bold>, <jats:bold>5<\/jats:bold>(<jats:bold>a\u2013b<\/jats:bold>), and <jats:bold>6<\/jats:bold>(<jats:bold>a\u2013b<\/jats:bold>) were confirmed by single crystal X\u2010ray. Docking studies identified compounds with favorable Gibbs free energy values for binding to histone deacetylase 8 (HDAC8), an enzyme targeted for anticancer drug development. These compounds bound to both the orthosteric and allosteric pockets of HDAC8, similar to Trichostatin A (TSA), an HDAC8 inhibitor. <jats:bold>6<\/jats:bold>(<jats:bold>a\u2013c<\/jats:bold>) contain hydroxyacetamide moiety as a zinc\u2010binding group, a phthalimide moiety as a capping group, and aminoacetamide moiety as a linker group, which are important for ligand\u2010receptor binding. \u0394<jats:italic>G<\/jats:italic> values indicated that compounds <jats:bold>5b<\/jats:bold>, <jats:bold>6b<\/jats:bold>, and <jats:bold>6c<\/jats:bold> had higher affinity for HDAC8 in the allosteric pocket compared to TSA. In vitro evaluation of inhibitory activities on HDAC8 revealed that compounds <jats:bold>3<\/jats:bold>(<jats:bold>a\u2013c<\/jats:bold>) and <jats:bold>5<\/jats:bold>(<jats:bold>a\u2013c<\/jats:bold>) showed similar inhibitory effects (IC<jats:sub>50<\/jats:sub>) ranging from 0.445 to 0.751\u2009\u03bcM. Compounds <jats:bold>6<\/jats:bold>(<jats:bold>a\u2013c<\/jats:bold>) showed better affinity, with <jats:bold>6a<\/jats:bold> (IC<jats:sub>50<\/jats:sub>\u2009=\u200928\u2009nM) and <jats:bold>6b<\/jats:bold> (IC<jats:sub>50<\/jats:sub>\u2009=\u20090.18\u2009\u03bcM) showing potent inhibitory effects slightly lower than TSA (IC<jats:sub>50<\/jats:sub>\u2009=\u200926\u2009nM). These findings suggest that the studied compounds hold promise as potential candidates for further biological investigations.<\/jats:p>","DOI":"10.1111\/cbdd.14323","type":"journal-article","created":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T06:10:10Z","timestamp":1693289410000},"page":"1367-1386","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Synthesis of N\u2010aminophalimides derived from \u03b1\u2010amino acids: Theoretical study to find them as <scp>HDAC8<\/scp> inhibitors by docking simulations and in vitro assays"],"prefix":"10.1111","volume":"102","author":[{"given":"Jos\u00e9 Eduardo","family":"Guzm\u00e1n\u00a0Ram\u00edrez","sequence":"first","affiliation":[{"name":"Departamento de Qu\u00edmica Centro de Investigaci\u00f3n y de Estudios Avanzados del Instituto Polit\u00e9cnico Nacional  Ciudad de M\u00e9xico Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4919-2985","authenticated-orcid":false,"given":"Teresa","family":"Mancilla\u00a0Percino","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Centro de Investigaci\u00f3n y de Estudios Avanzados del Instituto Polit\u00e9cnico Nacional  Ciudad de M\u00e9xico Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,8,28]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2018.10.037"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2016.03.003"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2012.04.060"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules15096588"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2008.9"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2018.12.039"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1055\/s\u20100028\u20101088013"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0108767394005726"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/j100785a001"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0040\u20104039(02)00119\u20103"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/ejoc.200300445"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00894\u2010011\u20101297\u20108"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/cbdd.13084"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.4155\/fmc\u20102016\u20100117"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2011.532"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471220639"},{"key":"e_1_2_11_18_1","volume-title":"Discovery studio visualizer, V19.1.0.18287","author":"Dassault Syst\u00e8mes BIOVIA","year":"2019"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi801610c"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molstruc.2016.10.052"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00044\u2010010\u20109492\u20101"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2010.03.080"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/ardp.200700158"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4360"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0021889812029111"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tet.2008.08.087"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms231710014"},{"key":"e_1_2_11_28_1","unstructured":"Frisch M. 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