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This process can be modulated by inhibiting \u03b1\u22122,6\u2010sialyltransferase 1 (ST6GAL1), one of the most important sialyltransferases. Most \u03b2\u2010galactoside ST6GAL1 inhibitors are polar CMP\u2010Neu5Ac derivatives with limited membrane permeability, a limitation shared by the noncarbohydrate inhibitor\n                    <jats:bold>JFD 00458<\/jats:bold>\n                    . Here, we designed\n                    <jats:bold>JFD 00458<\/jats:bold>\n                    analogs to improve permeability while maintaining ST6GAL1 inhibition and direct target engagement. Incorporation of sulfonic\u2010acid bioisosteres, particularly sulfonylureas, improved passive permeability, as measured by parallel artificial membrane permeability assay, with the best analog reaching log(P_app [cm\/s])\u2009=\u2009\u22124.3. Potency was also improved in an expanded series of sulfonylureas, with the best inhibitor displaying an IC\n                    <jats:sub>50<\/jats:sub>\n                    of 1.9\u2009\u00b5M. Microscale thermophoresis confirmed direct ST6GAL1 binding, with similar apparent\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>d<\/jats:sub>\n                    values of approximately 22\u201325\u2009\u00b5M for\n                    <jats:bold>JFD 00458<\/jats:bold>\n                    and the optimized sulfonylureas. Saturation transfer difference NMR identified the substituted phenoxy phenyl core as a common ST6GAL1\u2010contacting epitope, while closer contacts from the sulfonylurea\u2010linked aromatic substituents in\n                    <jats:bold>6d<\/jats:bold>\n                    and\n                    <jats:bold>6e<\/jats:bold>\n                    were associated with the highest inhibitory potency across the series. These results establish sulfonylureas as membrane\u2010permeable sulfonic\u2010acid bioisosteres and provide a structure\u2013activity framework for further ST6GAL1 inhibitor optimization.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70465","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T16:41:09Z","timestamp":1787762469000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sulfonylurea Bioisosteres of Sulfonic Acid in JFD 00458\u2010Based ST6GAL1 Inhibitors Enhance Membrane Permeability"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-6021-7888","authenticated-orcid":false,"given":"Natan","family":"Koraj","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry Faculty of Pharmacy University of Ljubljana  Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sushmaa","family":"Dangudubiyyam","sequence":"additional","affiliation":[{"name":"Univ. Lille CNRS UMR 8576 UGSF Unit\u00e9 de Glycobiologie Structurale et Fonctionnelle Facult\u00e9 des Sciences et Technologies University of Lille CNRS  Lille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8158-8716","authenticated-orcid":false,"given":"Adelyn M.","family":"Betances\u2010Mora","sequence":"additional","affiliation":[{"name":"Institute for Chemical Research CSIC \u2013 University of Seville  Seville Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ema","family":"Faganeli","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry Faculty of Pharmacy University of Ljubljana  Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1233-3799","authenticated-orcid":false,"given":"Anne","family":"Harduin\u2010Lepers","sequence":"additional","affiliation":[{"name":"Univ. Lille CNRS UMR 8576 UGSF Unit\u00e9 de Glycobiologie Structurale et Fonctionnelle Facult\u00e9 des Sciences et Technologies University of Lille CNRS  Lille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas","family":"Angulo","sequence":"additional","affiliation":[{"name":"Institute for Chemical Research CSIC \u2013 University of Seville  Seville Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tan Khanh","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Institute for Biocomputation and Physics of Complex Systems University of Zaragoza  Zaragoza Spain"},{"name":"Scientific Management Department Dong A University  Danang Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Bort\u2010Gri\u00f1\u00f3","sequence":"additional","affiliation":[{"name":"Institute for Biocomputation and Physics of Complex Systems University of Zaragoza  Zaragoza Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3122-9401","authenticated-orcid":false,"given":"Ramon","family":"Hurtado\u2010Guerrero","sequence":"additional","affiliation":[{"name":"Institute for Biocomputation and Physics of Complex Systems University of Zaragoza  Zaragoza Spain"},{"name":"Fundaci\u00f3n ARAID  Zaragoza Spain"},{"name":"Copenhagen Center for Glycomics\/Glycocalyx Department of Cellular and Molecular Medicine University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1768-8246","authenticated-orcid":false,"given":"Marko","family":"Anderluh","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry Faculty of Pharmacy University of Ljubljana  Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"2014","DOI":"10.3390\/cancers13092014","volume":"13","author":"Pietrobono S.","year":"2021","journal-title":"Cancers (Basel)"},{"key":"e_1_2_9_3_1","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/nrc3982","article-title":"Glycosylation in Cancer: Mechanisms and Clinical Implications","volume":"15","author":"Pinho S. 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