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One promising target is FabV, an enoyl\u2010acyl carrier protein reductase that is crucial for the survival of certain pathogenic Gram\u2010negative species such as the opportunistic nosocomial bacterium\n                    <jats:italic>P. aeruginosa<\/jats:italic>\n                    . Previously, our group investigated the structure\u2013activity relationship of diaryl ether\u2010based inhibitors of FabV and uncovered\n                    <jats:italic>p<\/jats:italic>\n                    \u2010\n                    <jats:italic>N<\/jats:italic>\n                    ,\n                    <jats:italic>N<\/jats:italic>\n                    \u2010dimethylsulfamoyl phenyl substitution as a privileged motif, exemplified by compounds\n                    <jats:bold>1a<\/jats:bold>\n                    (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20090.25\u2009\u03bcM) and\n                    <jats:bold>1e<\/jats:bold>\n                    (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20090.19\u2009\u03bcM). In the present study, we explored skeletal modifications of the diaryl ether scaffold with the aim of improving aqueous solubility of the compounds while maintaining potent activity. Our efforts uncovered compound\n                    <jats:bold>6k<\/jats:bold>\n                    (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20090.53\u2009\u03bcM), in which the alkyl chain is replaced by a 3\u2010cyanocyclobutyl group and which shows a fivefold increase in kinetic solubility compared to the parent compound\n                    <jats:bold>1a<\/jats:bold>\n                    . Similarly, benzene\u2010to\u2010pyridine replacement in the A\u2010ring led to significant solubility gains with minimal loss of potency. These results showcase an effective strategy for optimizing solubility in inhibitors targeting enzymes with highly lipophilic natural substrates.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70512","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T05:57:02Z","timestamp":1791439022000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Polarity\u2010Driven Scaffold Optimization of Diaryl Ether FabV Inhibitors to Enhance Aqueous Solubility"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0377-5659","authenticated-orcid":false,"given":"Radu\u2010George","family":"Bulai","sequence":"first","affiliation":[{"name":"Rega Institute for Medical Research Department of Pharmaceutical and Pharmacological Sciences Medicinal Chemistry KU Leuven  Leuven Belgium"},{"name":"Department of Biology Molecular Biotechnology of Plants and Micro\u2010organisms 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Plants and Micro\u2010organisms KU Leuven  Leuven Belgium"},{"name":"VIB Center for Microbiology VIB  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4673-2050","authenticated-orcid":false,"given":"Peter","family":"Verwilst","sequence":"additional","affiliation":[{"name":"Rega Institute for Medical Research Department of Pharmaceutical and Pharmacological Sciences Medicinal Chemistry KU Leuven  Leuven 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