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Humans have four isoenzymes of NEU, and their specific roles continue to be investigated. Isoenzyme\u2010selective inhibitors are needed as research tools and may lead to future therapeutics. A series of new candidate inhibitors are tested by replacing the C5\u2010amide of 2\u2010deoxy\u20102,3\u2010dididehydro\u2010\n                    <jats:italic>N<\/jats:italic>\n                    \u2010acetyl neuraminic acid with amide bioisosteres. Design of candidate inhibitors is accomplished using substituents that are components of previously identified NEU inhibitors combined with alternative amide bioisosteres. Compounds are tested for inhibition of the four human NEU, and inhibitory activities are compared to reference amide compounds. 1,4\u2010Disubstituted\u20101,2,3\u2010triazole is the best bioisostere observed for inhibitors of NEU1. Inhibitor\n                    <jats:bold>542<\/jats:bold>\n                    shows high potency for NEU1 (\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>i<\/jats:italic>\n                    <\/jats:sub>\n                    \u2009=\u20090.4\u2009\u00b1\u20090.1\u2009\u03bcM) and give significant improvement in selectivity compared to the reference amide compound\n                    <jats:bold>502<\/jats:bold>\n                    . Additionally, compound\n                    <jats:bold>542<\/jats:bold>\n                    has improved lipophilic characteristics, which could provide improved pharmacokinetic properties. Screening of these inhibitors also identify a selective NEU2 inhibitor\n                    <jats:bold>543<\/jats:bold>\n                    (\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>i<\/jats:italic>\n                    <\/jats:sub>\n                    \u2009=\u20092.6\u2009\u00b1\u20090.6\u2009\u03bcM), illustrating that amide bioisostere replacement can identify improved inhibitors for multiple NEU isoenzymes.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.202500099","type":"journal-article","created":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T14:29:18Z","timestamp":1744036158000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Improved C5\u2010Amide Bioisosteres for Human Neuraminidase 1 Inhibitors Based on 2\u2010Deoxy\u20102,3\u2010Didehydro\u2010\n                    <i>N<\/i>\n                    \u2010Acetyl Neuraminic Acid"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0318-4146","authenticated-orcid":false,"given":"Mostafa","family":"Radwan","sequence":"first","affiliation":[{"name":"Department of Chemistry University of Alberta  Edmonton Alberta T6G 2G2 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5241-8881","authenticated-orcid":false,"given":"Elisa G.","family":"Carvajal","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Alberta  Edmonton Alberta T6G 2G2 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3363-8708","authenticated-orcid":false,"given":"Christopher W.","family":"Cairo","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Alberta  Edmonton Alberta T6G 2G2 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,7]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.2576"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200501023"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/cb900266r"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr000407m"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2008.06.002"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2008.06.017"},{"key":"e_1_2_9_8_1","volume-title":"Essentials of Glycobiology","author":"Lewis A. 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