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Lipoxin\u2010A<jats:sub>4<\/jats:sub> (LXA<jats:sub>4<\/jats:sub>), an endogenous specialized pro\u2010resolving mediator (SPM), plays a central role in this process through activation of the ALX\/FPR2 receptor. However, its clinical application is limited by rapid metabolic degradation and poor in vivo stability. In this study, we report the design, asymmetric synthesis, and biological evaluation of novel 1,3\u2010 and 1,4\u2010disubstituted isoquinoline\u2010based analogues of LXA<jats:sub>4<\/jats:sub> (Isoq\u2010sLXms), designed to enhance metabolic stability. The synthetic route employed a palladium\u2010catalyzed Heck cross\u2010coupling and Ru(II)\u2010catalyzed asymmetric transfer hydrogenation, affording diastereomerically pure compounds. Biological assessment in THP\u20101 LUCIA monocytes demonstrated that several analogues, particularly (<jats:italic>1R<\/jats:italic>)\u2010<jats:bold>8<\/jats:bold>, significantly attenuate lipopolysaccharide (LPS)\u2010induced NF\u2010\u03baB activation and downstream pro\u2010inflammatory cytokine secretion, including IL\u20106, IL\u20101\u03b2, and TNF. Functional assays using ALX\/FPR2\u2010transfected HEK\u2010293 cells revealed that (<jats:italic>1R<\/jats:italic>)\u2010<jats:bold>8<\/jats:bold> acts as a partial agonist, supporting its role in engaging pro\u2010resolving signaling mechanisms. Safety profiling confirmed low cytotoxicity across physiologically relevant concentrations. These findings demonstrate that isoquinoline\u2010based LXA<jats:sub>4<\/jats:sub> mimetics retain and enhance key pro\u2010resolving bioactivities while offering improved stability and receptor selectivity. (<jats:italic>1R<\/jats:italic>)\u2010<jats:bold>8<\/jats:bold> emerges as a promising lead compound for the development of resolution\u2010directed therapeutics in the context of chronic inflammation.<\/jats:p>","DOI":"10.1002\/chem.202502091","type":"journal-article","created":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T05:00:11Z","timestamp":1756357211000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Asymmetric Synthesis and Biological Evaluation of 1,3\u2010 and 1,4\u2010Disubstituted Isoquinoline\u2010Containing Lipoxin A<sub>4<\/sub> Analogues"],"prefix":"10.1002","volume":"31","author":[{"given":"Denise","family":"Moran","sequence":"first","affiliation":[{"name":"Centre for Synthesis &amp; Chemical Biology School of Chemistry University College Dublin  Belfield Dublin 4 Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica","family":"de Gaetano","sequence":"additional","affiliation":[{"name":"UCD Conway Institute &amp; School of Biomolecular &amp; Biomedical Science University College Dublin  Belfield Dublin 4 Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Braden","family":"Millar","sequence":"additional","affiliation":[{"name":"UCD Conway Institute &amp; School of Biomolecular &amp; Biomedical Science University College Dublin  Belfield Dublin 4 Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine","family":"Godson","sequence":"additional","affiliation":[{"name":"UCD Conway Institute &amp; School of Medicine University College Dublin  Belfield Dublin 4 Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick J.","family":"Guiry","sequence":"additional","affiliation":[{"name":"Centre for Synthesis &amp; Chemical Biology School of Chemistry University College Dublin  Belfield Dublin 4 Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,8,27]]},"reference":[{"key":"e_1_2_15_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2010.04.005"},{"key":"e_1_2_15_2_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.307308"},{"key":"e_1_2_15_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.81.17.5335"},{"key":"e_1_2_15_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(84)91486-4"},{"key":"e_1_2_15_5_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI116601"},{"key":"e_1_2_15_6_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.156.6.2264"},{"key":"e_1_2_15_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00051a016"},{"key":"e_1_2_15_8_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.164.4.1663"},{"key":"e_1_2_15_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja00311a001"},{"key":"e_1_2_15_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(00)92034-3"},{"key":"e_1_2_15_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0957-4166(00)82153-9"},{"key":"e_1_2_15_12_1","doi-asserted-by":"publisher","DOI":"10.1039\/c0md00136h"},{"key":"e_1_2_15_13_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-051921-085407"},{"key":"e_1_2_15_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules29102233"},{"key":"e_1_2_15_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M002863200"},{"key":"e_1_2_15_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0090-6980(97)00001-4"},{"key":"e_1_2_15_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-894X(03)00667-X"},{"key":"e_1_2_15_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.plefa.2005.05.002"},{"key":"e_1_2_15_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.plefa.2005.05.020"},{"key":"e_1_2_15_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm030569l"},{"key":"e_1_2_15_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm060270d"},{"key":"e_1_2_15_22_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.10-175687"},{"key":"e_1_2_15_23_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.11-185017"},{"key":"e_1_2_15_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.05.003"},{"key":"e_1_2_15_25_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2012060550"},{"key":"e_1_2_15_26_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2017101112"},{"key":"e_1_2_15_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2008.01.013"},{"key":"e_1_2_15_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tet.2014.07.029"},{"key":"e_1_2_15_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.200900533"},{"key":"e_1_2_15_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2018.10.049"},{"key":"e_1_2_15_31_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c00403"},{"key":"e_1_2_15_32_1","doi-asserted-by":"publisher","DOI":"10.1055\/a-1992-7148"},{"key":"e_1_2_15_33_1","volume-title":"Foye's Principles of Medicinal Chemistry","author":"Lemke T. 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